马来酸氟伏沙明片联合氨磺必利治疗精神分裂症患者的疗效及安全性分析

目的:分析马来酸氟伏沙明片联合氨磺必利治疗精神分裂症患者的临床疗效及安全性。方法:选择我院2014年2月~2018年2月收治的182例精神分裂症患者,按随机数字表法分为对照组99例和研究组83例。对照组采用氨磺必利治疗,研究组在对照组基础上联合马来酸氟伏沙明片治疗。比较两组临床疗效,治疗前后血脂代谢、总胆汁酸(TBA)水平,阳性与阴性症状量表(PANSS)评分,生活质量,及不良发生情况。结果:治疗后,研究组总有效率为91.57%,显著高于对照组(P<0.05);两组治疗前后空腹血糖(FPG)、糖化血红蛋白(HbA1c)、甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白-C(LDL-C)、高密度脂蛋白-C(HLD-C)、总胆汁酸(TBA)水平比较均无统计学意义(P>0.05);两组治疗后PANSS评分均较治疗前显著下降,生活质量评分较治疗前均明显上升,且研究组PANSS评分显著低于对照组,而生活质量评分明显高于对照组,差异均有统计学意义(P<0.05)。治疗过程中,两组均有体重增加、口渴及便秘发生,两组不良反应发生情况比较差异无统计学意义(P>0.05)。结论:马来酸氟伏沙明片联合氨磺必利治疗能够提高精神分裂症患者疗效,对机体糖脂代谢及肝功能影响较小,有良好的用药安全性。     

Fluvoxamine rescues mitochondrial Ca transport and ATP production through σ1-receptor in hypertrophic cardiomyocytes

Aims

We previously reported that fluvoxamine, a selective serotonin reuptake inhibitor with high affinity for the σ₁-receptor (σ₁R), ameliorates cardiac hypertrophy and dysfunction via σ₁R stimulation. Although σ₁R on non-cardiomyocytes interacts with the IP₃ receptor (IP₃R) to promote mitochondrial Ca^2 + transport, little is known about its physiological and pathological relevance in cardiomyocytes.

Main methods

Here we performed Ca^2 + imaging and measured ATP production to define the role of σ₁Rs in regulating sarcoplasmic reticulum (SR)-mitochondrial Ca^2 + transport in neonatal rat ventricular cardiomyocytes treated with angiotensin II to promote hypertrophy.

Key finding

These cardiomyocytes exhibited imbalances in expression levels of σ₁R and IP₃R and impairments in both phenylephrine-induced mitochondrial Ca^2 + mobilization from the SR and ATP production. Interestingly, σ₁R stimulation with fluvoxamine rescued impaired mitochondrial Ca^2 + mobilization and ATP production, an effect abolished by treatment of cells with the σ₁R antagonist, NE-100. Under physiological conditions, fluvoxamine stimulation of σ₁Rs suppressed intracellular Ca^2 + mobilization through IP₃Rs and ryanodine receptors (RyRs). In vivo, chronic administration of fluvoxamine to TAC mice also rescued impaired ATP production.

Significance

These results suggest that σ₁R stimulation with fluvoxamine promotes SR-mitochondrial Ca^2 + transport and mitochondrial ATP production, whereas σ₁R stimulation suppresses intracellular Ca^2 + overload through IP₃Rs and RyRs. These mechanisms likely underlie in part the anti-hypertrophic and cardioprotective action of the σ₁R agonists including fluvoxamine.     

Simultaneous determination of plasma levels of fluvoxamine and of the enantiomers of fluoxetine and norfluoxetine by gas chromatography-mass spectrometry

A gas chromatographic-mass spectrometric method is presented which allows the simultaneous determination of the plasma concentrations of fluvoxamine and of the enantiomers of fluoxetine and norfluoxetine after derivatization with the chiral reagent, (S)-(-)-N-trifluoroacetylprolyl chloride. No interference was observed from endogenous compounds following the extraction of plasma samples from six different human subjects. The standard curves were linear over a working range of 10 to 750 ng/ml for racemic fluoxetine and norfluoxetine and of 50 to 500 ng/ml for fluvoxamine. Recoveries ranged from 50 to 66% for the three compounds. Intra- and inter-day coefficients of variation ranged from 4 to 10% for fluvoxamine and from 4 to 13% for fluoxetine and norfluoxetine. The limits of quantitation of the method were found to be 2 ng/ml for fluvoxamine and 1 ng/ml for the (R)- and (S)-enantiomers of fluoxetine and norfluoxetine, hence allowing its use for single dose pharmacokinetics. Finally, by using a steeper gradient of temperature, much shorter analysis times are obtained if one is interested in the concentrations of fluvoxamine alone.     

Fluvoxamine 对危重症患者外周血单核细胞功能的影响

目的：研究sigma-1 受体的激动剂fluvoxamine 对危重症患者外周血单核细胞功能的影响。方法：收集健康体检者和危重症 患者外周血，并采用淋巴细胞分离液离心，分离外周血单核细胞。将分离的单核细胞种植于96 孔细胞培养板中，种植密度为106/ 孔。然后，加入不同的浓度的fluvoxamine，共培养24 小时。在部分培养板中，同时加入1 uMsigma-1 受体拮抗剂BD1047。采用 MTT、ELISA 和荧光定量PCR 分别检测体检者与危重患者外周血单核细胞的细胞活性、炎症因子TNF-alpha、IL-1beta及抗炎因子 IL-10 水平的表达及fluvoxamine 对细胞活性、炎症因子TNF-alpha、IL-1beta及抗炎因子IL-10 水平的影响；采用Western blot 检测 fluvoxamine 对sigma-1 受体表达的影响。结果：Fluvoxamine 在极高剂量下才影响危重症患者外周单核细胞的活性。其IC50 值为 217.9 uM( 95%可区区间: 188.5-251.8 uM)。危重症患者的外周单核细胞分泌的促炎症因子TNF-alpha、IL-1beta的水平明显高于健康 体检患者，而fluvoxamine 能够抑制危重症患者单核细胞中TNF-alpha、IL-1beta等炎症因子的表达，促进抗炎症因子IL-10 的表达。但是 fluvoxamine 对健康人群的细胞因子没有影响。经1 uMBD1047 预处理以后，fluvoxamine 处理的单核细胞与未经fluvoxamine 处 理的细胞处于同样的活化状态。另外，fluvoxamine 和BD1047 并不影响sigma-1受体的表达。结论：Fluvoxamine 能够抑制危重症 患者的炎症活化状态，其效应可能与其激活sigma-1 受体有关。     

High-performance liquid chromatographic method to screen and quantitate seven selective serotonin reuptake inhibitors in human serum

A high-performance liquid chromatographic screening method (HPLC) is described for the determination of seven selective serotonin reuptake inhibitors (SSRIs) (fluvoxamine, milnacipran, paroxetine, sertraline, fluoxetine, citalopram, venlafaxine) and for three pharmacologically active N-demethylated metabolites (desmethylcitalopram, didesmethylcitalopram and norfluoxetine). A tricyclic antidepressant, clomipramine, was used as an internal standard. The method consists of liquid extraction of serum after alcalinisation at pH 9.50, followed by chromatography on a Beckman C₁₈ reversed-phase column. Compounds were detected at 200.4 nm. The standard curves were linear over a working range of 50–1000 ng/ml for fluvoxamine, 15–1000 ng/ml for fluoxetine, 25–500 ng/ml for norfluoxetine, 50–500 ng/ml for sertraline, 20–500 ng/ml for paroxetine, 25–550 ng/ml for citalopram, 25–750 ng/ml for desmethylcitalopram, 25–800 ng/ml for didesmethylcitalopram, 25–650 ng/ml for milnacipran, and 25–500 ng/ml for venlafaxine. The quantitation limits of the method were 15 ng/ml for fluoxetine, 20 ng/ml for paroxetine, 25 ng/ml for venlafaxine, norfluoxetine and citalopram, and its metabolites, 40 ng/ml for sertraline and 50 ng/ml for fluvoxamine. No interferences were noted with this sensitive and specific method which can be used for therapeutic drug monitoring.     

Fluvoxamine alleviates paclitaxel-induced neurotoxicity

Paclitaxel (Px) is an effective chemotherapeutic agent for the treatment of various cancers. However, it is often associated with neurological side effects, including chemotherapy-associated cognitive impairment (CACI), such as “chemobrain”. Previously, we reported that endoplasmic reticulum (ER) stress is involved in Px-induced neurotoxicity, and immunoglobulin heavy chain binding protein (BiP) inducer X (BIX) alleviates Px-induced neurotoxicity. However, BIX has not been used in clinical practice yet. We recently reported that fluvoxamine (Flv) alleviates ER stress via induction of sigma-1 receptor (Sig-1R). The purpose of this study was to investigate whether Flv could alleviate Px-induced neurotoxicity in vitro. SK-N-SH cells were pre-treated for 12 h with or without 10 μg/ml Flv followed by treatment with 1 μM Px with or without co-existence of 10 μg/ml Flv for 24 h. To investigate the involvement of Sig-1R in alleviation effect on Px-induced neurotoxicity,1 μM NE100, an antagonist of Sig-1R, was added for 24 h. Neurotoxicity was assessed using the MTS viability assay and ER stress-mediated neurotoxicity was assessed by evaluating the expression of C/EBP homologous protein (CHOP), cleaved caspase 4, and cleaved caspase 3.Pre-treatment with Flv significantly alleviated the induction of CHOP, cleaved caspase 4, and cleaved caspase 3 in SK-N-SH cells. At the same time, pre-treatment with Flv significantly induced Sig-1R in SK-N-SH cells. In addition, viability was significantly higher in Flv-treated cells than in untreated cells, which was reversed by treatment with NE100.Our results suggest that Flv alleviates Px-induced neurotoxicity in part through the induction of Sig-1R. Our findings should contribute to one of the novel approaches for the alleviation of Px-induced neurotoxicity, including chemobrain.     

3D structure modeling of cytochrome P450 2C19 and its implication for personalized drug design

Cytochrome P450 2C19 (CYP2C19) is a member of the cytochrome P-450 enzyme superfamily and plays an important role in the metabolism of drugs. In order to gain insights for developing personalized drugs, the 3D (dimensional) structure of CYP2C19 has been developed based on the crystal structure of CYP2C9 (PDB code 1R90), and its structure-activity relationship with the ligands of CEC, Fluvoxamine, Lescol, and Ticlopidine investigated through the structure-activity relationship approach. By means of a series of docking studies, the binding pockets of CYP2C19 for the four compounds are explicitly defined that will be very useful for conducting mutagenesis studies, providing insights into personalization of drug treatments and stimulating novel strategies for finding desired personalized drugs.