Antidepressants enhance the antinociceptive effects of carbamazepine in the acetic acid-induced writhing test in mice

Some antidepressants, as well as antiepileptics, are effective for treating pain of varying etiology. The present study was designed to characterize the antinociceptive effects of imipramine, a tricyclic antidepressant, fluvoxamine, a selective serotonin reuptake inhibitor, milnacipran, a serotonin noradrenaline reuptake inhibitor, and carbamazepine, an antiepileptic drug, using the acetic acid-induced writhing test in mice. Imipramine (1.25–10 mg/kg, i.p.), fluvoxamine (5–40 mg/kg, i.p.) and milnacipran (2.5–20 mg/kg, i.p.) all dose-dependently and significantly reduced the number of writhes induced by the injection of acetic acid (0.8% (v/v)), although the maximal effect of milnacipran was weaker than those of imipramine and fluvoxamine. Similarly, carbamazepine (5–20 mg/kg, i.p.) also showed a dose-dependent and significant antinociceptive effect. In combination studies, the co-administration of a sub-effective dose of carbamazepine (5 mg/kg, i.p.) with imipramine (1.25 and 2.5 mg/kg, i.p.), fluvoxamine (10 mg/kg, i.p.) or milnacipran (1.25 and 2.5 mg/kg, i.p.) significantly reduced the number of writhes. Additionally, the hole-board test revealed that the medications with significant antinociceptive effects barely produced changes in motor activity that could possibly affect writhing behavior. Thus, the present study demonstrated that the antinociceptive effect of carbamazepine is enhanced by combination with imipramine, fluvoxamine and milnacipran. Therefore, the combined therapy using antidepressants and carbamazepine may be useful clinically for the control of pain.     

氟伏沙明合并逍遥丸治疗抑郁症的临床观察

目的探讨氟伏沙明合并逍遥丸治疗抑郁症的疗效及安全性。方法将126例抑郁症患者随机分为研究组63例,对照组63例,分别给予氟伏沙明合并逍遥丸与单用氟伏沙明治疗,疗程8周。在治疗前及治疗后的第2、4、8周分别采用汉密尔顿抑郁量表(HAMD17)、汉密尔顿焦虑量表(HAMA)、临床疗效总评量表(CGI)进行疗效评定;用不良反应量表(TESS)评定不良反应。结果研究组痊愈41例,有效13例,有效率85.7%;对照组痊愈37例,有效7例,有效率71.0%,两组间有效率差异有统计学意义(χ2=4.013,P<0.05);与治疗前比较,两组治疗后的第2、4、8周HAMD17、HAMA及CGI评分比较,差异均具有统计学意义(P<0.01),研究组在治疗后4、8周末HAMD17和HAMA评分下降较对照组显著,两组间比较,差异具有统计学意义(P<0.05和P<0.01)。两组不良反应比较,研究组发生厌食和失眠的不良反应明显少于对照组,两组间比较差异均有统计学意义(P<0.05);结论氟伏沙明合并逍遥丸治疗抑郁症的疗效优于单用氟伏沙明,能提高临床有效率,且不良反应少,安全性高。     

Euprolactinemic gynecomastia and galactorrhea with risperidone-fluvoxamine combination

Risperidone is associated with hyperprolactinemia and its consequent symptoms such as gynecomastia, galactorrhea and sexual dysfunction in adults, and less so in adolescents. Rarely, serotonin reuptake inhibitors are also associated with such adverse effects. We report a case of gynecomastia and galactorrhea in an adolescent male while on a combination of risperidone and fluvoxamine, although the serum prolactin was within normal range.     

The Selective Serotonin Reuptake Inhibitor Paroxetine, but not Fluvoxamine, Decreases Methamphetamine Conditioned Place Preference in Mice

Monoamine transporters are the main targets of methamphetamine (METH). Recently, we showed that fluoxetine, a selective serotonin reuptake inhibitor (SSRI), decreased METH conditioned place preference (CPP), suggesting that serotonin transporter (SERT) inhibition reduces the rewarding effects of METH. To further test this hypothesis, in the present study we investigated the effects of additional SSRIs, paroxetine and fluvoxamine, on METH CPP in C57BL/6J mice. In the CPP test, pretreatment with 20 mg/kg paroxetine abolished the CPP for METH, whereas pretreatment with 100 mg/kg fluvoxamine prior to administration of METH failed to inhibit METH CPP. These results suggest that paroxetine, a medication widely used to treat depression, may be a useful tool for treating METH dependence. Further, these data suggest that molecules other than the SERT [such as G protein-activated inwardly rectifying K+ (GIRK) channels] whose activities are modulated by paroxetine and fluoxetine, but not by fluvoxamine, are involved in reducing METH CPP by paroxetine and fluoxetine.     

氟伏沙明联合无抽搐电休克或喹硫平治疗难治性强迫症

目的研究氟伏沙明联合无抽搐电休克、喹硫平对难治性强迫症患者的临床效果。方法选取2014-09—2016-09新乡医学院第二附属医院治疗的周期≥12周的78例难治性强迫症的患者,按照随机数字表方法分成2组,喹硫平联合氟伏沙明治疗的39例患者为对照组,无抽搐电休克联合氟伏沙明治疗的39例患者为观察组,对比2组临床效果、TESS评分及生活质量。结果观察组耶鲁-布朗强迫量表总分(8.45±7.20)分和汉密尔顿抑郁(29.20±1.10)分、汉密尔顿焦虑(28.50±1.40)分均较对照组低(P0.01);2组8、12周后TESS评分对比均无显著差异(P0.05);观察组总体健康评分(84.55±14.33)分,高于对照组的(65.35±13.02)分(P0.01)。结论难治性强迫症者应用无抽搐电休克联合氟伏沙明治疗,能够缓解强迫症状,改善不良强迫带来的不良情绪,且不良反应少,利于提高生活质量,有一定临床应用价值。     

A pharmacokinetic and pharmacodynamic evaluation of the combined administration of alprazolam and fluvoxamine

We have assesed the pharmacokinetic and pharmacodynamic interaction between fluvoxamine, a serotonin reuptake inhibitor, and alprazolam, a triazolobenzodiazepine.Healthy men took fluvoxamine maleate daily for 10 days (50 mg on days 1–3, 100 mg on days 4–10) (n=20), 1 mg of alprazolam four times daily for four days (days 7–10 of the study period) (n=20), or a combination of the two (n=20), according to a parallel study design. Alprazolam and fluvoxamine concentrations were measured in serial plasma samples by HPLC and gas chromatography respectively, and psychomotor performance and memory were assessed on days 1, 7, and 10.Fluvoxamine increased plasma alprazolam concentrations by 100%. The mean apparent half-life of alprazolam was increased from 20 h to 34 h after fluvoxamine co-administration.The increased plasma concentrations of alprazolam resulted in significantly greater reductions in psychomotor performance evident on day 10. Mean fluvoxamine plasma concentrations were about 25% lower in those who took the combination than in those who took only fluvoxamine; this was more likely due to heterogeneity between the treatment groups than to an effect of alprazolam.The dosage of alprazolam should be reduced during co-administration with fluvoxamine.     

Serotonin function in panic disorder: a double blind placebo controlled study with fluvoxamine and ritanserin

In order to evaluate serotonin (5-HT) function in panic disorder, a double blind placebo controlled study was conducted with ritanserin, a specific 5-HT₂ receptor antagonist, and fluvoxamine, a selective 5-HT reuptake inhibitor, in 60 patients with panic disorder. Patients were treated for 8 weeks with 150 mg fluvoxamine, 20 mg ritanserin or placebo; these dose levels were reached after 1 week. In addition, as an index of 5-HT function in panic disorder, plasma concentration of -endorphin, cortisol and 5-hydroxyindolacetic-acid (5-HIAA) were measured. Furthermore, 5-HT uptake in blood platelets was assessed. Noradrenergic function was assessed by measuring plasma MHPG concentration. In addition, plasma melatonin concentration was measured. Treatment with fluvoxamine resulted in a profound reduction in the number of panic attacks, followed by a decrease in avoidance behavior. Treatment with ritanserin appeared to be ineffective. During treatment no significant changes were observed in plasma concentrations of -endorphin, cortisol, 5-HIAA and MHPG. With respect to 5-HT kinetics in blood platelets, a substantial increase in K_m was observed after treatment with fluvoxamine, whereas V_max decreased. After treatment with fluvoxamine, plasma concentration of melatonin was significantly increased, which suggests that melatonin synthesis is in part under serotonergic control. The findings of the present study do not support the hypothesis that 5-HT₂ receptors are supersensitive in patients suffering from panic disorder, but allow no conclusions about the involvement of other 5-HT receptor subtypes.     

High occupancy of sigma-1 receptors in the human brain after single oral administration of fluvoxamine: a positron emission tomography study using [11C]SA4503.

BACKGROUND: Sigma-1 receptors might be implicated in the pathophysiology of psychiatric diseases, as well as in the mechanisms of action of some selective serotonin reuptake inhibitors (SSRIs). Among the several SSRIs, fluvoxamine has the highest affinity for sigma-1 receptors (Ki = 36 nM), whereas paroxetine shows low affinity (Ki = 1893 nM). The present study was undertaken to examine whether fluvoxamine binds to sigma-1 receptors in living human brain. METHODS: A dynamic positron emission tomography (PET) data acquisition using the selective sigma-1 receptor ligand [(11)C]SA4503 was performed with arterial blood sampling to evaluate quantitatively the binding of [(11)C]SA4503 to sigma-1 receptors in 15 healthy male volunteers. Each subject had two PET scans before and after randomly receiving a single dose of either fluvoxamine (50, 100, 150, or 200 mg) or paroxetine (20 mg). The binding potential of [(11)C]SA4503 in 9 regions of the brain was calculated by a 2-tissue 3-compartment model. In addition, we examined the effects of functional polymorphisms of the sigma-1 receptor (SIGMAR1) gene on the binding potential of [(11)C]SA4503. RESULTS: Fluvoxamine bound to sigma-1 receptors in all brain regions in a dose-dependent manner, whereas paroxetine did not bind to sigma-1 receptors. However, there was no association between the SIGMAR1 gene polymorphism GC-241-240TT and binding potential. CONCLUSIONS: The study demonstrated that fluvoxamine bound to sigma-1 receptors in living human brain at therapeutic doses. These findings suggest that sigma-1 receptors may play an important role in the mechanism of action of fluvoxamine.     

Physiologically based pharmacokinetic modeling of altered tizanidine systemic exposure by CYP1A2 modulation: Impact of drug-drug interactions and cigarette consumption

Tizanidine is an alpha2-adrenergic agonist, used to treat spasticity associated with multiple sclerosis and spinal injury. Tizanidine is primarily metabolized by CYP1A2 and is considered a sensitive index substrate for this enzyme. The physiologically based pharmacokinetic (PBPK) modeling platform Simcyp® was used to evaluate the impact of CYP1A2 modulation on tizanidine exposure through drug-drug interactions (DDIs) and host-dependent habits (cigarette smoking). A PBPK model was developed to predict tizanidine disposition in healthy volunteers following oral administration. The model was verified based on agreement between model-simulated and clinically observed systemic exposure metrics (C_max, AUC). The model was then used to carry-out DDI simulations to predict alterations in tizanidine systemic exposure when co-administered with various CYP1A2 perpetrators including competitive inhibitors (fluvoxamine, ciprofloxacin), a mechanism-based inhibitor (rofecoxib), and an inducer (rifampin). Additional simulations were performed to evaluate the impact of cigarette smoking on systemic exposure. Under each scenario, the PBPK model was able to capture the observed fold changes in tizanidine C_max and AUC of tizanidine when coadministered with CYP1A2 inhibitors or inducers. These results add to the available research findings in the literature on PBPK predictions of drug-drug interactions and illustrate the potential application in drug development, specifically to support product labeling.