Antidepressant Sertraline Is a Broad-Spectrum Inhibitor of Enteroviruses Targeting Viral Entry through Neutralization of Endolysosomal Acidification

Enterovirus 71 (EV71) is an etiological agent of hand foot and mouth disease and can also cause neurological complications in young children. However, there are no approved drugs as of yet to treat EV71 infections. In this study, we conducted antiviral drug screening by using a Food and Drug Administration (FDA)-approved drug library. We identified five drugs that showed dose-dependent inhibition of viral replication. Sertraline was further characterized because it exhibited the most potent antiviral activity with the highest selectivity index among the five hits. The antiviral activity of sertraline was noted for other EV serotypes. The drug’s antiviral effect is not likely associated with its approved indications as an antidepressant and its mode-of-action as a selective serotonin reuptake inhibitor. The time-of-addition assay revealed that sertraline inhibited an EV71 infection at the entry stage. We also showed that sertraline partitioned into acidic compartments, such as endolysosomes, to neutralize the low pH levels. In agreement with the findings, the antiviral effect of sertraline could be greatly relieved by exposing virus-infected cells to extracellular low-pH culture media. Ultimately, we have identified a use for an FDA-approved antidepressant in broad-spectrum EV inhibition by blocking viral entry through the alkalization of the endolysosomal route.     

合曲林联合多沙唑嗪控释片与舍曲林单用治疗早泄的临床研究

【目的】比较舍曲林联合多沙唑嗪控释片与单用舍曲林治疗早泄的疗效及不良反应。【方法】男科门诊无器质性病变的早泄患者34例,随机分成单用组、联合组各17例,单用组1：1服舍曲林50mg（性生活前4～6h服用）,1次／日,联合组口服舍曲林50mg,每日一次（性生活前4～6h服用）和多沙唑嗪控释片4mg,每日一次,观察12周。比较两组治疗前后的平均阴道内射精潜伏期、国际勃起功能指数（IIEF）问卷中的性交满意度评分、每周性交频率以及治疗期间的不良反应,患者及其配偶对性生活的满意程度。【结果】单用组、联合组两组患者平均阴道内射精潜伏期在治疗后均显著增加,而联合组较单用组增加更显著（P=0．016）;患者的性生活满意度两组均有显著性提高,组间比较差异无显著性（P=0．139）;治疗后每周性交频率两组均显著增多,联合组患者每周性交频率增加更明显（P=0．0107）;不良反应两组比较差异无显著性（P=0．0641）。【结论】舍曲林联合多沙唑嗪控释片较舍曲林单用治疗早泄具有更好的疗效,同时不良反应的发生率无明显增加。     

盐酸舍曲林的合成

α-萘酚和邻二氯苯经付-克芳基化、胺基化、脱酰基等反应制得顺式外消旋舍曲林,再经D-(一)-扁桃酸拆分后成盐即可制得盐酸舍曲林,总收率25%.操作简便,反应条件温和,适合放大制备.     

盐酸舍曲林治疗抑郁症合并冠心病患者疗效分析

目的观察抑郁症合并冠心病患者盐酸舍曲林治疗前后抑郁状态及一氧化氮(NO)、内皮素(ET)的变化,为评价盐酸舍曲林治疗抑郁症合并冠心病患者的疗效及安全性提供依据。方法将64例抑郁症合并冠心病患者随机分为研究组和对照组,2组均为32例。2组患者均给予冠心病常规治疗,研究组患者每晚加用盐酸舍曲林50～200 mg,对照组每晚加用安慰剂1～4片,总疗程为4周。2组患者治疗前及治疗后第4周末进行汉密尔顿抑郁量表(HAMD)评分,并监测治疗前后NO、ET的变化。结果治疗4周后,研究组HAMD评分为10.12±1.46,与对照组18.84±1.52比较,差别有统计学意义(P<0.01);治疗后研究组NO含量为(112.18±47.30)μmol.L-1,较治疗前(75.37±27.80)μmol.L-1显著升高,差别有统计学意义(P<0.05),但与对照组(102.40±50.27)μmol.L-1比较差别无统计学意义(P>0.05);治疗后研究组ET含量为(56.50±10.02)μg.L-1,较治疗前(62.05±10.45)μg.L-1显著降低(P<0.05),但与对照组(57.14±14.14)μg.L-1比较差别无统计学意义(P>0.05)。结论盐酸舍曲林可以明显改善抑郁症合并冠心病患者的抑郁症状,且不增加心血管系统的治疗风险。     

Sertraline inhibits the transport of PAT1 substrates in vivo and in vitro

Background and Purpose

Intestinal nutrient transporters may mediate the uptake of drugs. The aim of this study was to investigate whether sertraline interacts with the intestinal proton-coupled amino acid transporter 1 PAT1 (SLC36A1).

Experimental Approach

In vitro investigations of interactions between sertraline and human (h)PAT1, hSGLT1 (sodium-glucose linked transporter 1) and hPepT1 (proton-coupled di-/tri-peptide transporter 1) were conducted in Caco-2 cells using radiolabelled substrates. In vivo pharmacokinetic investigations were conducted in male Sprague–Dawley rats using gaboxadol (10 mg·kg⁻¹, p.o.) as a PAT1 substrate and sertraline (0–30.6 mg·kg⁻¹). Gaboxadol was quantified by hydrophilic interaction chromatography followed by MS/MS detection.

Key Results

Sertraline inhibited hPAT1-mediated L-[³H]-Pro uptake in Caco-2 cells. This interaction between sertraline and PAT1 appeared to be non-competitive. The uptake of the hSGLT1 substrate [¹⁴C]-α–methyl-D-glycopyranoside and the hPepT1 substrate [¹⁴C]-Gly-Sar in Caco-2 cells was also decreased in the presence of 0.3 mM sertraline. In rats, the administration of sertraline (0.1–10 mM, corresponding to 0.3–30.6 mg·kg⁻¹, p.o.) significantly reduced the maximal gaboxadol plasma concentration and AUC after its administration p.o.

Conclusions and Implications

Sertraline is an apparent non-competitive inhibitor of hPAT1-mediated transport in vitro. This inhibitory effect of sertraline is not specific to hPAT1 as substrate transport via hPepT1 and hSGLT1 was also reduced in the presence of sertraline. In vivo, sertraline reduced the amount of gaboxadol absorbed, suggesting that the inhibitory effect of sertraline on PAT1 occurs both in vitro and in vivo. Hence, sertraline could alter the bioavailability of drugs absorbed via PAT1.     

艾司西酞普兰治疗老年慢性心力衰竭并抑郁障碍的近其疗效和安全性随机对照研究

目的研究艾司西酞普兰治疗老年慢性心力衰竭合并抑郁障碍的疗效和安全性。方法采用随机对照、开放性设计,将98例在三甲综合医院接受门诊和住院治疗的患者随机分为两组,艾司西酞普兰组49例,舍曲林组49例,疗程8周。用汉密尔顿抑郁量表（HAMD-17）评估抗抑郁疗效,用副反应量表（TESS）评估患者的药物不良反应。结果艾司西酞普兰组治疗期间脱落率与舍曲林组比较,差异无统计学意义（18．36％比22．45％,P=0．616）;起效时间早于舍曲林组,HAMD评分在第2周末（F=7．311,P=0．008）、第4周末（F=4．646,P=0．034）低于合曲林组,但到第6周末（F=0．899,／9=0．345）和第8周末（F=1．320,P=0．253）两组差异无统计学意义。第8周末时,艾司西酞普兰组痊愈12例（24．49％）,显著进步22例（44．90％）,进步3例（6．12％）,无效12例（24．49％）;舍曲林组痊愈10例（20．41％）,显著进步23例（46．94％）,进步2例（4．08％）,无效14例（28．57％）。两组痊愈率（χ2=0．23,P=0．63）和显效率（x2=0．21,P=0．65）差异无统计学意义,不良反应发生率亦无统计学差异（26．53％比38．78％,P=0．396）。两种抗抑郁药物对左心室射血分数（LVEF）的改善无统计学差异（F=1．405,P=0．239）。心电图校正的QT间期（QTc）在两组患者治疗前后（F=0．069,P=0．793）和两组间（F=0．319,P=0．574）均无统计学差异。结论艾司西酞普兰治疗老年慢性心力衰竭合并抑郁障碍的疗效和安全性与舍曲林相当,但起效更快。     

舍曲林联合阿立哌唑治疗强迫症的临床观察

目的 探讨舍曲林联合阿立哌唑治疗强迫症的临床疗效及耐受性.方法 86例强迫症患者随机分为观察组(n=43)和对照组(n=43),观察组用舍曲林和阿立哌唑联合治疗,对照组单用舍曲林治疗,观察治疗12周.于治疗前、治疗4周末、8周末、12周末分别用耶鲁布朗强迫量表(Y-BOCS)评定强迫症状、用汉密尔顿焦虑量表(HAMA)评定焦虑症状、用副反应量表(TESS)评定治疗4周末、8周末、12周末的药物不良反应.结果 Y-BOCS总分治疗前、治疗4周末两组间差异无统计学意义(P＞0.05),治疗8周末、12周末两组间差异有统计学意义(P＜0.05); HAMA总分治疗前两组差异无统计学意义(P＞0.05),治疗4周末、8周末、12周末差异均有统计学意义(P＜0.05);治疗4周末、8周末、12周末两组间TESS总分差异均无统计学意义(P＞0.05).结论 舍曲林联合阿立哌唑治疗强迫症效果良好,不良反应无增加.     

Risks and benefits of medications for panic disorder: a comparison of SSRIs and benzodiazepines

Introduction: Panic disorder (PD) is a prevalent and disabling anxiety disorder that can be treated effectively. Selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines are among the most frequently prescribed drugs for PD. In this article, the authors review the current evidence on efficacy, adverse events, and limitations of these two treatment options.

Areas covered: MEDLINE/Pubmed and Web of Science databases were searched for open or placebo-controlled trials on SSRIs and/or benzodiazepines in PD treatment.

Expert opinion: The literature search yielded 4,957 articles related to the theme. Of these, 24 articles were included in this review. Despite their usefulness in PD, SSRIs are associated with a delay of several weeks in onset of therapeutic effect and have the potential to exacerbate anxiety and panic early in the treatment course. Benzodiazepines present rapid onset of action, but can cause tolerance and dependence. Despite strong evidence of the effectiveness of SSRIs and benzodiazepines in the treatment of PD, few trials have performed head-to-head comparisons of these two drug classes. Future studies on the pharmacological treatment of PD should make direct comparisons of risks, benefits, and limitations of each group. This could help improve the evidence-based pharmacotherapy of PD.     

Efficacy of sertraline for bulimia nervosa

OBJECTIVE: The current study examined the efficacy of sertraline in the treatment of individuals diagnosed with bulimia nervosa. METHOD: Eighteen women enrolled in an 8-week open trial of sertraline. Eating disorder psychopathology and depressive symptoms were assessed at baseline and at the end of the trial using both semistructured interviews and self-report questionnaires. RESULTS: Findings indicated significant reductions in eating disorder psychopathology, including the number of binges and purges per week, as well as significant reductions in depressive symptoms. In addition, participants did not experience significant weight gain or any other sertraline side effect assessed at the end of the trial compared with baseline. DISCUSSION: Findings from the current study indicate that sertraline is efficacious in the treatment of bulimia nervosa. A double-blind controlled trial of sertraline is recommended for future research.