BACKGROUND: G protein-coupled receptor kinase 2 (GRK2) could participate in the regulation of diverse cells via interacting with non-G-protein-coupled receptors. In the present work, we explored how paroxetine, a GRK2 inhibitor, modulates the differentiation and activation of immune cells in rheumatoid arthritis (RA). METHODS: The blood samples of healthy individuals and RA patients were collected between July 2021 and March 2022 from the First Affiliated Hospital of Anhui Medical University. C57BL/6 mice were used to induce the collagen-induced arthritis (CIA) model. Flow cytometry analysis was used to characterize the differentiation and function of dendritic cells (DCs)/T cells. Co-immunoprecipitation was used to explore the specific molecular mechanism. RESULTS: In patients with RA, high expression of GRK2 in peripheral blood lymphocytes, accompanied by the increases of phosphatidylinositol 3 kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR). In animal model, a decrease in regulatory T cells (T regs ), an increase in the cluster of differentiation 8 positive (CD8 + ) T cells, and maturation of DCs were observed. Paroxetine, when used in vitro and in CIA mice, restrained the maturation of DCs and the differentiation of CD8 + T cells, and induced the proportion of T regs . Paroxetine inhibited the secretion of pro-inflammatory cytokines, the expression of C-C motif chemokine receptor 7 in DCs and T cells. Simultaneously, paroxetine upregulated the expression of programmed death ligand 1, and anti-inflammatory cytokines. Additionally, paroxetine inhibited the PI3K-AKT-mTOR metabolic pathway in both DCs and T cells. This was associated with a reduction in mitochondrial membrane potential and changes in the utilization of glucose and lipids, particularly in DCs. Paroxetine reversed PI3K-AKT pathway activation induced by 740 Y-P (a PI3K agonist) through inhibiting the interaction between GRK2 and PI3K in DCs and T cells. CONCLUSION Paroxetine exerts an immunosuppressive effect by targeting GRK2, which subsequently inhibits the metabolism-related PI3K-AKT-mTOR pathway of DCs and T cells in RA.
G-Protein-Coupled Receptor Kinase 2/metabolism* ; Arthritis, Rheumatoid/immunology* ; Animals ; Dendritic Cells/metabolism* ; Paroxetine/therapeutic use* ; Proto-Oncogene Proteins c-akt/metabolism* ; Mice ; Humans ; Mice, Inbred C57BL ; Signal Transduction/drug effects* ; Male ; Phosphatidylinositol 3-Kinases/metabolism* ; Lymphocyte Activation/drug effects* ; Female ; T-Lymphocytes/metabolism* ; Middle Aged

OBJECTIVE: To investigate the clinical effect and adverse reactions of dapoxetine hydrochloride versus paroxetine in the treatment of primary premature ejaculation by cross-comparison. METHODS: Based on the clinic-visit time, we equally randomized 148 patients with primary premature ejaculation into groups A and B for a cross-comparison test, the former treated with paroxetine at 20 mg once nightly and the latter with dapoxetine hydrochloride at 30 mg on demand, both for 6 successive weeks, during which we observed the therapeutic effects and adverse reactions. Following 4 weeks of drug discontinuance, we administered dapoxetine hydrochloride at 30 mg on demand for group A and paroxetine at 20 mg once nightly for group B, both for another 6 successive weeks, followed by observation and comparison of the therapeutic effects and adverse reactions. RESULTS: There were no statistically significant differences in the initial characteristics of the two groups of patients (P > 0.05). Compared with the baseline, the mean intra-vaginal ejaculation latency time (IELT) was dramatically improved after treatment in both groups A (4.43 min) and B (7.12 min), increased by 3.99% and 6.72%, respectively (P<0.001). The patients treated with paroxetine showed significantly longer IELT than those taking dapoxetine hydrochloride in both groups (P<0.001). Findings of the Premature Ejaculation Profile (PEP) and spouses' conditions indicated significant improvement after treatment in the average scores of the four indicators of PEP, that is, perceived control over ejaculation, ejaculation-related personal distress, satisfaction with sexual intercourse and ejaculation-related interpersonal difficulty, as well as in the overall experience and partner's satisfaction and orgasm frequency. Adverse reactions to medication were found in 20.8% of the cases in group A and 9.7% in group B, but none was serious. Preference survey following drug withdrawal revealed a preference for paroxetine (61.9%) over dapoxetine (26.8%), and that only a few of the patients thought of the two drugs as comparable or both ineffective. CONCLUSION In term of overall effectiveness, paroxetine was superior to dapoxetine in the treatment of primary premature ejaculation. And the patients obviously preferred the former to the latter, which might be partly attributed to the higher price of dapoxetine.
Humans ; Benzylamines/therapeutic use* ; Male ; Premature Ejaculation/drug therapy* ; Naphthalenes/therapeutic use* ; Paroxetine/therapeutic use* ; Adult ; Treatment Outcome ; Middle Aged ; Young Adult ; Selective Serotonin Reuptake Inhibitors/therapeutic use*

Since exploding rates of modern mental diseases, application of antidepressants has increased. Worryingly, the antidepressant-induced liver injury has gradually become a serious health burden. Furthermore, since most of the knowledge about antidepressant hepatotoxicity are from pharmacovigilance and clinical case reports and lack of observational studies, the underlying mechanisms are poorly understood and there is a lack of efficient treatment strategies. In this study, antidepressant paroxetine directly triggered inflammasome activation evidenced by caspase-1 activation and downstream effector cytokines interleukin(IL)-1β secretion. The pretreatment of echinatin, a bioactive component of licorice, completely blocked the activation. This study also found that echinatin effectively inhibited the production of inflammasome-independent tumor necrosis factor α(TNF)-α induced by paroxetine. Mechanistically, the accumulation of mitochondrial reactive oxygen species(mtROS) was a key upstream event of paroxetine-induced inflammasome activation, which was dramatically inhibited by echinatin. In the lipopolysaccharide(LPS)-mediated idiosyncratic drug-induced liver injury(IDILI) model, the combination of LPS and paroxetine triggered aberrant activation of the inflammasome to induce idiosyncratic hepatotoxicity, which was reversed by echinatin pretreatment. Notably, this study also found that various bioactive components of licorice had an inhibitory effect on paroxetine-triggered inflammasome activation. Meanwhile, multiple antidepressant-induced aberrant activation of the inflammasome could be completely blocked by echinatin pretreatment. In conclusion, this study provides a novel insight for mechanism of antidepressant-induced liver injury and a new strategy for the treatment of antidepressant-induced hepatotoxicity.
Animals ; Humans ; Mice ; Antidepressive Agents/adverse effects* ; Chemical and Drug Induced Liver Injury, Chronic/prevention & control* ; Glycyrrhiza/chemistry* ; Inflammasomes/drug effects* ; Interleukin-1beta/metabolism* ; Lipopolysaccharides/toxicity* ; Mice, Inbred C57BL ; NLR Family, Pyrin Domain-Containing 3 Protein ; Paroxetine/adverse effects* ; Tumor Necrosis Factor-alpha ; Chalcones/therapeutic use*

OBJECTIVETo investigate the clinical value of Paroxetine combined with mid-frequency electrical pulse acupoint stimulation (EPAS) in the treatment of premature ejaculation (PE).

METHODSTotally 69 PE patients were equally assigned to receive oral Paroxetine 20 mg/d, mid-frequency EPAS, or oral Paroxetine 10 mg/d combined with mid-frequency EPAS (P + EPAS) , all for 8 weeks. We obtained the intravaginal ejaculation latency time (IELT) and Chinese Index of Premature Ejaculation (CIPE-5) scores of the patients before and after treatment, and compared adverse reactions among the three groups of patients.

RESULTSOne patient of the Paroxetine group gave up treatment because of abdominal pain and nausea. Compared with the baseline, the patients in the Paroxetine, EPAS, and P + EPAS groups all showed markedly increased IELT ([0.92 ± 0.11] vs [4.07 ± 0.11] min, P < 0.01; [0.92 ± 0.12] VS [2.78 ± 0.17] min P < 0.05; [0.91 ± 0.09] vs [5.31 ± 0.13], P < 0.01) and decreased CIPE-5 scores (12.5 ± 3.0 vs 22.0 ± 2.1, P < 0.01; 12.8 ± 2.9 vs 19.5 ± 1.9, P > 0.05; 13.1 ± 2.8 vs 25.2 ± 2.1, P 0.01), with statistically significant differences between the P + EPAS group and the other two (P < 0.05). The total effectiveness rate was 95.7% in the P + EPAS group, remarkably higher than in the Paroxetine (72.7%, P < 0.05) and the EPAS group (47.8, P < 0.01).

CONCLUSIONOral Paroxetine combined with mid-frequency EPAS has a higher safety and efficacy than either Paroxetine or EPAS alone in the treatment of PE.

Acupuncture Points ; Aged ; Combined Modality Therapy ; methods ; Ejaculation ; Electroacupuncture ; methods ; Humans ; Male ; Paroxetine ; therapeutic use ; Premature Ejaculation ; therapy ; Serotonin Uptake Inhibitors ; therapeutic use ; Treatment Outcome

OBJECTIVETo explore the efficacy of jieyu granule (JG) combined Paroxetine in treating refractory depression (RD) patients of yin deficiency inner heat syndrome (YDIHS).

METHODSSeventy RD patients of YDIHS were randomly assigned to the experimental group (JG combined Paroxetine) and the control group (Chinese medical placebo combined Paroxetine), 35 cases in each group. Hamilt Depression Rating Scale and Hamilton Anxiety Scale were used before treatment, and at the weekend of the 2nd, 4th, and 8th week, respectively.

RESULTSIn the experimental group, 32 patients completed the trial and 3 patients dropped out. In the control group, 33 patients completed the trial and 2 patients dropped out. At the end of the 8th week of the treatment, the total score of Hamilt Depression Rating Scale was (14.75 +/- 7.85) in the experimental group, lower than that of the control group (19. 06 +/- 8. 31, P <0.05). At the end of the 2nd, 4th, and 8th week of the treatment, the score of Hamilton Anxiety Scale was 17.03 +/- 4.25, 14.50 +/- 5. 13, and 11.03 +/- 4.88, respectively in the experimental group, lower than that of the control group at each corresponding time point (19. 60 +/-3. 96, 17. 12 +/- 4.14, 14.64 +/- 4.47, P <0.05, P <0.01).

CONCLUSIONThe efficacy of JG combined Paroxetine for treating RD patients of YDIHS was superior to that of using Paroxetine alone.

Adult ; Antidepressive Agents, Second-Generation ; therapeutic use ; Depressive Disorder, Treatment-Resistant ; diagnosis ; drug therapy ; Drugs, Chinese Herbal ; therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Paroxetine ; therapeutic use ; Phytotherapy ; Treatment Outcome ; Yin Deficiency ; diagnosis ; drug therapy

OBJECTIVETo explore the personality-adjusting effect of electro-acupuncture treatment for depression and compared this treatment with paroxetine treatment.

METHODSA non-blinded, randomized controlled trial was adopted. Sixty depressed patients, who met trial criteria, were randomly assigned to the treatment and the control groups. In the treatment group, electro-acupuncture treatment was used, and paroxetine treatment was used in the control group. During the 24-week study period, 12 patients dropped out and 48 patients completed the study. The Minnesota Multiple Personality Inventory (MMPI) was adopted as the evaluation tool. At the same time, the Self-rating Depression Scale (SDS), Self-rating Anxiety Scale (SAS) and Montgomery-Asberg Depression Rating Scale (MADRS) were used to evaluate the psychological state. Evaluations were done before and after treatment.

RESULTSAfter treatment, patients' psychological state improved significantly in both groups (P<0.01). For the treatment group, within-group comparison between baseline and after 24 weeks of treatment showed that severity of depression had significantly decreased (P<0.01). MADRS and SDS scores decreased significantly (P<0.05) and MMPI subscale scores for hypochondriasis, depression, psychopathic deviate, psychasthenia, social introversion and fake decreased significantly (P<0.05). For the control group, severity of depression also decreased significantly. MADRS and SDS scores decreased significantly (P<0.05); and MMPI subscale scores for hypochondriasis, depression, hysteria, paranoia, and psychasthenia decreased significantly (P<0.05). Between-group comparison demonstrated that for the MMPI subscales paranoia and social introversion, the decrease of score was greater in the treatment group than in the control group (P<0.05). However, there were no other significant differences between the control group and the treatment group.

CONCLUSIONElectro-acupuncture is effective for treating depression and affects personality traits.

Case-Control Studies ; Demography ; Depression ; drug therapy ; psychology ; therapy ; Electroacupuncture ; Female ; Humans ; Male ; Middle Aged ; Paroxetine ; therapeutic use ; Patient Dropouts ; Personality ; Personality Inventory ; Psychiatric Status Rating Scales

OBJECTIVETo assess the effects of apolipoprotein E (APOE) polymorphism on the susceptibility of depression and the efficacy of antidepressants.

METHODSA total of 275 patients with depression, who met the diagnostic criteria of both CCMD-3 and DSM-4, were randomly assigned into venlafaxine group (n=136)and paroxetine group(n=139). Another 202 healthy subjects were enrolled as the control group. Hamilton Rating Scale for Depression (HAMD)-17 was adopted as the primary rating instrument to evaluate the severity of depression on the baseline and the end of the 1st, 2nd, 4th, 6th week after treatment, respectively. HAMD scores ≤7 was defined as remission, and the reduction of HAMD scores ≥50% was defined as response while <50% was defined as invalid. PCR-restriction fragment length polymorphisms (PCR-RFLP) was applied to detect the genetic polymorphism of the APOE in the case groups and control group.

RESULTSIn the venlafaxine group, the remission rate was 52.9%(n=72), the response rate was 26.5%(n=36), and the invalid rate was 20.6%(n=28), whereas the corresponding data in the paroxetine group wee 42.4%(n=59), 31.7%(n=44), and 25.9% (n=36), respectively. There were no significant differences in the efficacy between the two groups(p>0.05). In the venlafaxine group, there were no significant differences in the genotypes and the allele distribution frequency of APOEΕ2/Ε3/Ε4 between the remitters, nonremitters, and healthy controls at the end of the 6th week(p>0.05), but there was significant differences in the allele distribution frequency between the nonremitters and healthy controls(p=0.02). In paroxetine group, there were no significant differences in the genotypes and the allele distribution frequency of APOEΕ2/Ε3/Ε4 among the remitters, nonremitters and healthy controls at the end of the 6th week(p>0.05), but there were significant differences in the allele distribution frequency between the nonremitters and healthy controls (p=0.04); in addition, there were also significant differences in Ε2/Ε3 and Ε4 allele between the two groups (p=0.014).

CONCLUSIONSThe APOE gene may not play a major role in the pathogenesis of major depression. The efficacy of venlafaxine is same as paroxetine after treatment for six weeks. The APOE (Ε2+Ε3) allele may be an indicator of the bad efficacy of paroxetine treatment.

Adolescent ; Adult ; Aged ; Antidepressive Agents ; therapeutic use ; Apolipoproteins E ; genetics ; Cyclohexanols ; therapeutic use ; Depression ; drug therapy ; genetics ; Female ; Genetic Predisposition to Disease ; Humans ; Male ; Middle Aged ; Paroxetine ; therapeutic use ; Polymorphism, Genetic ; Treatment Outcome ; Venlafaxine Hydrochloride ; Young Adult

OBJECTIVETo compare the differences in the efficacy on agitated depression among the alliance therapy of acupuncture and seroxat, the alliance therapy of electroacupuncture and seroxat and the simple application of seroxat.

METHODSOne hundred and two cases were randomized into a medication group, a conventional acupuncture + medication group and an electroacupuncture + medication group, 34 cases in each one. In the medication group, seroxat was prescribed for oral administration, once per day. In the conventional acupuncture + medication group, seroxat was applied in combination with the conventional acupuncture therapy, in which, Baihui (GV 20) and Yintang (EX-HN 3) were taken as the main acupoints. In the electroacupuncture + medication group, seroxat was applied in combination with electroacupuncture, in which, on the basic therapeutic program as the conventional acupuncture + medication group, the electric stimulation was attached to Baihui (GV 20) and Yintang (EX-HN 3). Acupuncture was applied once every two days, the treatment of 6 weeks made one session and one session treatment was required in the research. Before and after treatment, the clinical global impression (CGI) and the World Health Organization Quality of Life-BREF (WHOQOL-BREF) were adopted for the assessment in each group.

RESULTS(1) CGI comparison: the severity of illness (SI) after treatment was all alleviated significantly for the patients in three groups as compared with that before treatment (all P < 0.001), but the difference was not significant statistically among groups (P > 0.05). The global improvement (GI) was different significantly among three groups (P < 0.05), in which GI in the electroacupuncture + medication group was the best, that in the conventional acupuncture + medication group was taken second place. The total improvement rates were 100.0% (29/29), 96.9% (31/32) and 93.5% (29/31) separately. The difference in the efficacy index (EI) was not significant statistically among three groups (P > 0.05). Concerning to the adverse events, there were 1 case (mild insomnia) in the medication group, 1 case (moderate anorexia) in the conventional acupuncture + medication group and 2 cases (mild insomnia and dry mouth) in the electroacupuncture + medication group. (2) WHOQOL-BREF comparison: compared with those before treatment, all the indices in the electroacupuncture + medication group were increased significantly after treatment (all P < 0.01); except the indices in the physiological field, all the other indices were improved in the conventional acupuncture + medication group after treatment (P < 0.01, P < 0.05); the scores only in the physiological field and social field were higher significantly than those before treatment in the medication group (P < 0.01, P < 0.05). After treatment, the statistically significant difference was displayed only in the psychological field among three groups (P < 0.05), in which, the improvement in the electroacupuncture + medication group was the best, that in the conventional acupuncture + medication group was taken second place and that in the medication group was the worst.

CONCLUSIONEither the alliance therapy of acupuncture and medication or the simple oral administration of seroxat improves the overall efficacy and the quality of life in the patients with agitated depression. The efficacy of the alliance therapy of acupuncture and medication is superior to the simple oral administration of seroxat and the efficacy of electroacupuncture is superior to the conventional acupuncture therapy.

Acupuncture Therapy ; Adolescent ; Adult ; Antidepressive Agents ; therapeutic use ; Combined Modality Therapy ; Depression ; drug therapy ; therapy ; Female ; Humans ; Male ; Middle Aged ; Paroxetine ; therapeutic use ; Quality of Life ; Young Adult

OBJECTIVETo validate the therapeutic efficacy of paroxetine in the treatment of premature ejaculation (PE).

METHODSEighty PE patients up to the inclusion criteria were equally randomized to an experimental and a control group. We observed all the patients for 4 weeks and recorded the baseline data on intravaginal ejaculatory latency time (IELT) and sexual satisfaction scores, followed by oral medication of paroxetine at 20 mg/d for the patients in the experimental group and placebo for the controls. Thirty days after the treatment, we again recorded IELT and sexual satisfaction scores of the patients.

RESULTSAfter the treatment, the experimental group showed significantly prolonged IELT ([5.75 +/- 1.24] min) and increased sexual satisfaction score (6.4 +/- 1.2) as compared with the baseline data ([0.89 +/- 0.21] min and [2.7 +/- 0.9]) (P < 0.01). The control group exhibited no significant differences before and after the medication either in the mean IELT or in sexual satisfaction scores ([1.06 +/- 0.28] min vs [0.97 +/- 0.18] min and 3.6 +/- 1.3 vs 3.1 +/- 1.1, P > 0.05).

CONCLUSIONOral medication of paroxetine at 20 mg/d for 30 days could improve IELT and sexual satisfaction in PE patients.

Adult ; Ejaculation ; Humans ; Male ; Paroxetine ; therapeutic use ; Serotonin Uptake Inhibitors ; therapeutic use ; Sexual Dysfunction, Physiological ; drug therapy ; Treatment Outcome ; Young Adult

OBJECTIVETo evaluate the efficacy and safety of Chaihu Xiaoyao Mixture (CXM) for the treatment of major depressive disorder (MDD).

METHODSOne hundred and ninety patients with MDD were randomly assigned to two groups, the test group and the control group. They were treated by paroxetine combined with CXM or placebo for 8 weeks. The therapeutic efficacy was evaluated at the end of the 2nd, 4th and 8th week by scoring according Hamilton Rating Scale for Depression (HAMD-17) and Clinical Global Impression (CGI) scale, and the adverse reaction was scaled by Treatment Emergent Symptoms Scale (TESS).

RESULTSFollow-up study was completed in 89/92 patients in the test group, and 93/98 patients in the control group, with 3 and 5 cases dropping, respectively. The effective rate in the two groups was 84.8% and 71.4%, and the cure rate was 69.6% and 55.1%, respectively, which were significantly higher in the test group than in the control group (chi2=4.92, P<0.05; chi2=4.22, P<0.05). As compared with the baseline, significant differences in HAMD-17 total score and scores of its various factors as well as the CGI score were shown in both groups after 2, 4 and 8's week treatment (P<0.01). Comparison between groups showed that significant differences presented in HAMD-17 total score and CGI score at the end of the 8th week (P<0.01), while comparison of adverse reactions between groups showed insignificantly statistical difference (P>0.05).

CONCLUSIONCombined treatment of CXM and paroxetine is more effective than that with paroxetine alone in treating MDD, and it could enhance the clinical efficacy with higher safety.

Adolescent ; Adult ; Aged ; Antidepressive Agents, Second-Generation ; therapeutic use ; Depressive Disorder, Major ; drug therapy ; Drug Therapy, Combination ; Drugs, Chinese Herbal ; therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Paroxetine ; therapeutic use ; Phytotherapy ; Young Adult