Molecularly Imprinted Polymer Nanoparticles for Selective Solid Phase Extraction of Fluvoxamine in Human Urine and Plasma.

In this work, the molecularly imprinted polymer nanoparticles (MIP-NPs) for the selective determination of fluvoxamine have been described. The polymer nanoparticles were synthesized by the polymerization of methacrylic acid as a functional monomer, ethylene glycol dimethacrylate as a cross-linker, 2,2-azobisisobutyronitrile as an initiator and fluvoxamine as a template molecule. The MIP-NPs were characterized using techniques that included Fourier transform infrared (FT-IR) spectroscopy and scanning electron microscopy (SEM). Imprinted fluvoxamine molecules were removed from the polymeric structure using acetonitrile in methanol (2:8; v/v) as the eluting solvent. The linear dynamic range for fluvoxamine was 10-1200 µg L-1. The developed method was successfully applied to the extraction of fluvoxamine in complex biological samples.

Development of a fluvoxamine detection system using a Quenchbody, a novel fluorescent biosensor.

The misuse of psychotropic drugs intended for medical treatment represents a recent worldwide public health concern. Quenchbody (Q-body) is a novel fluoroimmunosensor that can detect an antigen immediately without additional reagents or washing steps. Here, we describe creating Q-bodies for the detection of the antidepressant fluvoxamine (FLV) and determining optimal conditions to achieve the highest fluorescence intensity (FI). We prepared five Q-bodies with the fluorophore labeled at either the N- or C- terminus and with different linker lengths. Fluorescence was measurable within minutes, indicating the interaction of Q-bodies with FLV. The normalized FI (FI ratio) of the N-terminus labeled Q-body increased approximately 1.5-fold upon FLV addition; Q-bodies labeled at the C-terminus did not significantly increase FI. Among the fluorescence dyes used in this study, Rhodamine 6G labeled Q-body showed the best FI ratio. EC50 values of the N-terminus labeled Q-bodies were similar (23.2-224nM) regardless of linker length or labeling dye. We examined whether the Q-body could be applicable to serum matrix instead of phosphate-buffered saline. The intact serum interfered strongly with the Q-body fluorescence. However, the FI ratios of the Q-body for FLV-spiked serum filtrate, for which proteins were removed by filtration, showed a dose-dependency for detecting FLV levels. Deproteinization, which does not interfere with Q-body fluorescence measurements, is likely necessary to detect serum FLV with high sensitivity. This study demonstrates the potential of Q-body probes as a tool towards developing creative immunoassay applications.

Selective serotonin reuptake inhibitors and venlafaxine in pregnancy: Changes in drug disposition.

BACKGROUND: Pregnancy may cause changes in drug disposition. The clinical consequences may be profound and even counterintuitive; in some cases pregnant women may need more than twice their usual drug dose in order to maintain therapeutic drug levels. For antidepressants, evidence on drug disposition in pregnancy is scarce. The aim of this study was to determine the effects of pregnancy on serum levels of selective serotonin reuptake inhibitors (SSRIs) and venlafaxine in a large and naturalistic patient material, in order to provide tentative dose recommendations for pregnant women. METHODS: Using patient data from two routine therapeutic drug monitoring (TDM) services in Norway with linkage to the national birth registry, dose-adjusted serum drug concentrations of SSRIs and venlafaxine during pregnancy were compared to the women's own baseline (non-pregnant) values, using a linear mixed model. FINDINGS: Overall, the TDM databases contained 196,726 serum concentration measurements from 54,393 women. After data linkage and drug selection (SSRIs or venlafaxine only), we identified 367 analyses obtained from a total of 290 pregnancies in 281 women, and 420 baseline observations from the same women. Serum concentrations in the third trimester were significantly lower than baseline for paroxetine (-51%; 95% confidence interval [CI], -66%, -30%; p<0.001), fluvoxamine (-56%; CI, -75%, -23%; p = 0.004) and citalopram (-24%; CI, -38%, -7%; p = 0,007), and higher than baseline for sertraline (+68%; CI, +37%, +106%; p<0.001). For escitalopram, fluoxetine and venlafaxine concentrations did not change significantly. CONCLUSIONS: For paroxetine and fluvoxamine the pronounced decline in maternal drug serum concentrations in pregnancy may necessitate a dose increase of about 100% during the third trimester in order to maintain stable concentrations. For fluoxetine, venlafaxine, citalopram, escitalopram and sertraline, the present study indicates that dose adjustments are generally not necessary during pregnancy.

Determination of fluvoxamine maleate in human urine and human serum using alkaline KMnO4 -rhodamine B chemiluminescence.

The flow-injection chemiluminescence (FI-CL) behavior of a gold nanocluster (Au NC)-enhanced rhodamine B-KMnO4 system was studied under alkaline conditions for the first time. In the present study, the as-prepared bovine serum albumin-stabilized Au NCs showed excellent stability and reproducibility. The addition of trace levels of fluvoxamine maleate (Flu) led to an obvious decline in CL intensity in the rhodamine B-KMnO4 -Au NCs system, which could be used for quantitative detection of Flu. Under optimized conditions, the proposed CL system exhibited a favorable analytical performance for Flu determination in the range 2 to 100 µg ml-1 . The detection limit for Flu measurement was 0.021 µg ml-1 . Moreover, this newly developed system revealed outstanding selectivity for Flu detection when compared with a multitude of other species, such as the usual ions, uric acid and a section of hydroxy compounds. Additionally, CL spectra, UV-visible spectroscopes and fluorescence spectra were measured in order to determine the possible reaction mechanism. This approach could be used to detect Flu in human urine and human serum samples with the desired recoveries and could have promising application under physiological conditions.

Use of three-compartment physiologically based pharmacokinetic modeling to predict hepatic blood levels of fluvoxamine relevant for drug-drug interactions.

Using a three-compartment physiologically based pharmacokinetic (PBPK) model and a tube model for hepatic extraction kinetics, equations for calculating blood drug levels (Cb s) and hepatic blood drug levels (Chb s, proportional to actual hepatic drug levels), were derived mathematically. Assuming the actual values for total body clearance (CLtot ), oral bioavailability (F), and steady-state distribution volume (Vdss ), Cb s, and Chb s after intravenous and oral administration of fluvoxamine (strong perpetrator in drug-drug interactions, DDIs), propranolol, imipramine, and tacrine were simulated. Values for Cb s corresponded to the actual values for all tested drugs, and mean Chb and maximal Chb -to-maximal Cb ratio predicted for oral fluvoxamine administration (50 mg twice-a-day administration) were nearly 100 nM and 2.3, respectively, which would be useful for the predictions of the DDIs caused by fluvoxamine. Fluvoxamine and tacrine are known to exhibit relatively large F values despite having CLtot similar to or larger than hepatic blood flow, which may be because of the high liver uptake (almost 0.6) upon intravenous administration. The present method is thus considered to be more predictive of the Chb for perpetrators of DDIs than other methods.

Therapeutic Drug Monitoring of Selective Serotonin Reuptake Inhibitors in Elderly Patients.

BACKGROUND: Elderly patients are at increased risk for elevated serum concentrations from treatment with selective serotonin reuptake inhibitors (SSRIs). The aim of this study was to examine the use of therapeutic drug monitoring (TDM) of SSRIs in elderly compared with younger patients. METHODS: All serum concentration measurements of SSRIs (escitalopram, citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) performed at our laboratory in 2011 were included. The use of TDM (relative frequency) in older versus younger patients was examined by comparing the use of TDM in patients aged 60 years or older with that in patients younger than 60 years and by evaluating the use of TDM relative to age (age groups in decennials). The number of patients with an SSRI dispensed by prescription in the same region and period (the Norwegian Prescription Database) was used as reference. Additionally, the number of samples above the upper limit of the recommended reference range in patients aged 60 years or older and patients younger than 60 years was evaluated. RESULTS: TDM of an SSRI had been performed in 6333 patients. For all SSRIs, the use of TDM was significantly lower (8.2% versus 10.6% for citalopram, 10.0% versus 13.8% for escitalopram, 8.6% versus 17.0% for fluoxetine, 5.6% versus 10.3% for paroxetine, and 8.1% versus 15.0% for sertraline) in patients aged 60 years or older compared with those younger than 60 years (P < 0.001). There was a gradual decline in the use of TDM with increasing age, with a 3-fold difference between the youngest (10-19) and oldest (90+) patients (P < 0.0001). The percentage of samples above the upper limit of the recommended reference range was 2-fold higher in patients aged 60 years or older (6.7%) compared with patients younger than 60 (3.4%) years (P < 0.0001). CONCLUSIONS: Clinical follow-up of patients with TDM of SSRIs is less frequent in older patients compared with younger patients. This is in contrast to the general guidelines for TDM where patients of advanced age are considered of particular importance to monitor closely.

Fluvoxamine by itself has potential to directly induce long QT syndrome at supra-therapeutic concentrations.

Fluvoxamine is one of the typical selective serotonin-reuptake inhibitors. While its combined use with QT-prolonging drugs has been contraindicated because of the increase in plasma concentrations of such drugs, information is still limited whether fluvoxamine by itself may directly prolong the QT interval. We examined electropharmacological effects of fluvoxamine together with its pharmacokinetic profile by using the halothane-anesthetized dogs (n = 4). Fluvoxamine was intravenously administered in three escalating doses of 0.1, 1 and 10 mg/kg over 10 min with a pause of 20 min between the doses. The low dose provided therapeutic plasma drug concentration, whereas the middle and high doses attained approximately 10 and 100 times of the therapeutic ones, respectively. Supra-therapeutic concentration of fluvoxamine exerted the negative chronotropic, inotropic and hypotensive effects; and suppressed the atrioventricular nodal and intraventricular conductions, indicating inhibitory actions on Ca2+ and Na+ channels, whereas it delayed the repolarization in a reverse use-dependent manner, reflecting characteristics of rapidly activating delayed rectifier K+ current channel-blocking property. Fluvoxamine prolonged the terminal repolarization phase at 100 times higher concentration than the therapeutic, indicating its proarrhythmic potential. Thus, fluvoxamine by itself has potential to directly induce long QT syndrome at supra-therapeutic concentrations.

Bcl1 polymorphism of the glucocorticoid receptor gene and treatment response to milnacipran and fluvoxamine in Japanese patients with depression.

BACKGROUND: Polymorphisms in the glucocorticoid receptors (GRs) have been widely studied with rather less emphasis on relating their differences with possible pharmacological treatment outcomes. The purpose of this study was to investigate whether Bcl1 polymorphisms of GRs are associated with the antidepressant effect of milnacipran, a serotonin noradrenaline reuptake inhibitor (SNRI), and fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), in Japanese patients with depression. METHODS: Patients were prescribed either milnacipran (n = 98) or fluvoxamine (n = 95). The severity of depression was assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS) at 0, 1, 2, 4 and 6 weeks of treatment. RESULTS: Both agents were similarly effective in reducing MADRS scores in 6 weeks. In all subjects receiving milnacipran or fluvoxamine, our data showed no significant interaction between Bcl1 polymorphisms and therapeutic effects. However, when milnacipran- and fluvoxamine-treated subjects were analyzed independently, patients with G allele in Bcl1 polymorphism had a significantly better response to fluvoxamine than those with C/C genotype. On the other hand, no significant relationship was found between treatment response to milnacipran and Bcl1 polymorphism. CONCLUSION: Bcl1 polymorphism may be one of the genetic factors in predicting treatment response to SSRI but not SNRI in Japanese patients with depression.

Clozapine-associated development of second-onset obsessive compulsive symptoms in schizophrenia: impact of clozapine serum levels and fluvoxamine add-on.

Among antiserotonergic second generation antipsychotics (SGA), particularly treatment with clozapine (CLZ) is associated with the development of second-onset obsessive compulsive symptoms (OCS) in schizophrenia. However, less is known regarding the factors that increase the individual susceptibility for the development of SGA-associated second-onset OCS in schizophrenia. Here we present the case of a 29-year-old female patient with disorganized schizophrenia who exhibited OCS due to fluvoxamine-induced elevation of CLZ serum levels via inhibition of CYP 1A2 und 2C19. The severity of the observed OCS featured an association with CLZ serum levels. The case illustrates the interaction between fluvoxamine add-on and CLZ serum levels on the development of OCS in schizophrenia and emphasizes the need of regular therapeutic drug monitoring.

Potassium permanganate-acridine yellow chemiluminescence system for the determination of fluvoxamine, isoniazid and ceftriaxone.

Based on the oxidation of acridine yellow by permanganate in basic medium, a new chemiluminescence system was developed for the sensitive determination of some important drugs. The remarkable inhibiting effect of fluvoxamine, ceftriaxone and isoniazid on this reaction was applied to their detection. A possible mechanism was proposed for this system based on chemiluminescence emission wavelengths and experimental observations. Under optimum conditions, calibration graphs were obtained for 1 × 10(-9) to 1 × 10(-6) mol/L of fluvoxamine; 2 × 10(-8) to 8 × 10(-6) mol/L of ceftriaxone and 5 × 10(-8) to 4 × 10(-5) mol/L of isoniazid. This proposed method was satisfactorily used in the determination of these drugs in pharmaceutical samples and human urine and serum.

[Addition of fluvoxamine to clozapine: theory and practice]. / Additie van fluvoxamine aan clozapine: theorie en praktijk.

BACKGROUND: The addition of fluvoxamine to clozapine induces a rise of plasma concentrations of clozapine. This enables the prescription of a lower number of clozapine tablets, yet it attains sufficient clozapine plasma concentrations, and facilitates treatment adherence. AIM: Providing practical advice for the practical implementation of the addition of fluvoxamine to clozapine. METHOD: A review of the literature with Ovid Medline and the presentation of a case series (N=7). RESULTS: Addition of 25 or 50 mg fluvoxamine induces a mean rise of plasma concentrations of clozapine with a factor 2-3, probably even higher with the addition of 100 mg. However, the range of this factor varies considerably between individuals. The use of clozapine and fluvoxamine at the same time possibly has a favourable impact on the metabolic side-effects of clozapine. CONCLUSION: Addition of fluvoxamine to clozapine can lead to a dangerous rise of clozapine plasma concentrations. However, it can also be used to prescribe a lower number of clozapine tablets and to facilitate treatment adherence. A sufficient safety margin should be taken and regular control of clozapine plasma concentrations is mandatory.

Plasma fluvoxamine levels and OCD symptoms/response in adult patients.

OBJECTIVE: In this study, we explored the possible relationships between plasma fluvoxamine levels and clinical features and/or response in adult obsessive-compulsive disorder (OCD) patients treated with this drug for 6 months. METHODS: Twenty OCD outpatients of both sexes who were already taking fluvoxamine (mean dose ± SD: 216.7 ± 86.2) for at least 4 weeks were included in the study. The severity of OCD was assessed by means of the Yale-Brown obsessive-compulsive scale (Y-BOCS). The fluvoxamine plasma levels were measured by high-performance liquid chromatography analysis. All evaluations were performed after 4 weeks (t1) and 6 months (t2) of fluvoxamine intake. RESULTS: The plasma levels of fluvoxamine remained stable at the two assessment times, with no sex-related differences. Sixteen (80%) patients responded to treatment as shown by the significant (>35%) decrease of the Y-BOCS total score. Men's compulsions improved more than those of women. Significant and positive correlations were detected between fluvoxamine plasma levels at t1 and t2 and the difference (delta) of the Y-BOCS total and compulsion subscale scores between t1 and t2. Another significant, albeit negative, correlation was measured between the difference of the compulsion subscale score and the difference of fluvoxamine levels at t1 and t2. CONCLUSIONS: These findings underline the potential importance of evaluating fluvoxamine plasma levels in OCD and their relationships with the clinical response that may be gender-related on specific symptoms.

Pharmacokinetics and distribution of fluvoxamine to the brain in rats under oxidative stress.

The effects of oxidative stress (OS) on the pharmacokinetics of fluvoxamine (FLV), particularly on FLV distribution in the plasma, were studied in ferric-nitrilotriacetate-induced OS rat models (OS rats). The study protocol involved a continuous FLV infusion (25.0 µg/kg/min). The resulting mean plasma FLV concentration measured in steady state OS rats was 0.13 ± 0.01 µg/mL, which was significantly lower than plasma concentrations measured in control rats (0.19 ± 0.01 µg/mL). Moreover, the mean FLV concentration in the OS rat brain (0.51 ± 0.08 µg/g) was determined to be approximately half the concentration in control rat brains (0.95 ± 0.11 µg/g). The FLV concentrations in both the unbound fraction of plasma and erythrocytes of OS rats were significantly greater than that of control rats. These results suggest the potential attenuation of FLV's pharmacological effects in patients under OS.

The relationship between clinical pharmacokinetics of aripiprazole and CYP2D6 genetic polymorphism: effects of CYP enzyme inhibition by coadministration of paroxetine or fluvoxamine.

PURPOSE: To investigate the effects of coadministration of paroxetine or fluvoxamine on the pharmacokinetics of aripiprazole in healthy adult Japanese with different CYP2D6 genotypes. METHODS: Fourteen CYP2D6 extensive metabolizer (EM) and 14 CYP2D6 intermediate metabolizer (IM) subjects were coadministered a single oral dose of aripiprazole 3 mg after steady-state plasma concentrations of the SSRIs paroxetine (20 mg/day) or fluvoxamine (100 mg/day) were reached by repeated oral doses for 6-7 days. The pharmacokinetics of aripiprazole with and without coadministration of SSRIs were compared according to CYP2D6 genotypes. RESULTS: Coadministration of paroxetine, a potent CYP2D6 inhibitor, decreased systemic clearance (CL/F) of aripiprazole by 58 and 23% in CYP2D6 EMs and IMs, respectively, demonstrating that the percentage inhibition of CYP2D6 activity by coadministration of paroxetine was apparently greater in CYP2D6 EMs than in IMs. Coadministration of fluvoxamine, a less potent CYP3A4 inhibitor, decreased the CL/F of aripiprazole by 39% in CYP2D6 EMs and 40% in IMs, indicating the same inhibitory effect on CYP enzymes, regardless of the CYP2D6 genotype. Percent contribution of CYP2D6 to total CL/F (CYP2D6 plus CYP3A4) of aripiprazole estimated as a reduced percentage of CL/F by CYP enzyme inhibition was 62% for CYP2D6 EMs and 24% for IMs in paroxetine coadministration, and 40% for CYP2D6 EMs and 18% for IMs in fluvoxamine coadministration. CONCLUSIONS: There were marked differences in the degree of influence of paroxetine coadministration on the pharmacokinetics of aripiprazole between CYP2D6 EMs and IMs, but no apparent differences were found between two CYP2D6 genotypes in fluvoxamine coadministration. Aripiprazole can be used safely in combination with SSRIs that have a CYP enzyme-inhibitory action.

Decrease in brain distribution of fluvoxamine in experimental hyperlipidemic rats.

PURPOSE: Many clinical reports and trials have suggested that fluvoxamine (FLV) reduces plasma lipoprotein levels. However, few studies have reported the effect of plasma lipoproteins on FLV pharmacokinetics. The aim of the present study was to investigate the affinities of FLV to plasma lipoproteins and the effect of plasma lipoproteins on the biodistribution of FLV using an experimental hyperlipidemic (HL) rat model. METHODS: HL rats were prepared by intraperitoneal administration of Poloxamer-407 solution (1.0 g/kg). In vitro protein binding and distribution of FLV in plasma lipoproteins were determined in control and HL rats. In vivo pharmacokinetic study (intravenous administration of FLV, 5.0 mg/kg) and biodistribution analysis for brain and liver at a steady state (infusion, 1.5 mg/kg/hr, 6 hrs) were also performed. RESULTS: The plasma protein binding of FLV was around 83% and 95% in control and HL rats, respectively, whereas the FLV recoveries in triglyceride-rich lipoprotein fractions were increased in HL. Therefore, the elevation of lipoproteins was likely responsible for the increase in protein binding in HL. After intravenous administration, the area under the plasma concentration vs. time curve (AUC) in HL was 3.9-fold greater than that in control rats, whereas the distribution ratio of FLV plasma concentration to the brain at a steady state was decreased to approximately 20% of that of the control. CONCLUSIONS: FLV has an affinity to plasma lipoproteins, and their elevation might decrease the FLV biodistribution to brain; the plasma lipoprotein levels could not be found to correlate positively with the FLV pharmacokinetic effect in brain, but rather may attenuate it.

Impact of sample hemolysis on drug stability in regulated bioanalysis.

Being regulated by agencies' guidances, the importance of a robust validated bioanalytical method is crucial as it may impact the validity of the pharmacokinetic data generated. During blood collection and processing, the presence of hemolyzed plasma samples may occur and as a result its impact must be investigated to ensure method robustness. Indeed, hemolyzed samples may affect the analyte recovery efficiency, as well as the chromatography. Furthermore, the stability of an analyte in hemolyzed plasma can be an issue as analyte degradation may occur. In this article we report two case studies where the analyte instability was a result of sample hemolysis. A description of the appropriate actions undertaken for the resolution of the issue will be discussed.

CYP2D6 genotype and smoking influence fluvoxamine steady-state concentration in Japanese psychiatric patients: lessons for genotype-phenotype association study design in translational pharmacogenetics.

The CYP2D6 enzyme is a capacity-limited high-affinity drug elimination pathway that metabolizes numerous psychiatric medicines. The capacity-limited nature of this enzyme suggests that drug dose may serve as an important factor that influence genotype-phenotype associations. However, dose dependency of CYP2D6 genotype contributions to drug elimination, and its interaction with environmental factors (e.g., smoking) did not receive adequate attention in translational study designs. Fluvoxamine is a selective serotonin reuptake inhibitor antidepressant. Fluvoxamine concentration is one of the factors previously linked to clinical remission in moderate to severe depression. We investigated the joint effect of smoking (an inducer of CYP1A2) and CYP2D6 genotype on interindividual variability in fluvoxamine steady-state concentration. Fluvoxamine concentration was measured in 87 patients treated with 50, 100, 150 or 200 mg/d. While CYP2D6 genotype significantly influenced fluvoxamine concentration in all four dose groups (p < 0.05), the percentage variance explained (R²) by CYP2D6 decreased as the dose of fluvoxamine increased. Smoking status (nonsmokers vs. smoking 20 or more cigarettes/d) significantly affected fluvoxamine concentration in the 50 mg/d group only (p = 0.005). Together, CYP2D6 genotype and smoking status explained 23% of the variance in fluvoxamine concentration but only at the low 50 mg/d dose group. These findings contribute to evidence-based and personalized choice of fluvoxamine dose using smoking status and CYP2D6 genetic variation. Additionally, these data lend evidence for drug dose as an important variable in translational pharmacogenetic study design and pharmaceutical phenotype associations with capacity-limited drug metabolism pathways such as CYP2D6.

[First death case of serotonin syndrome in Japan induced by fluvoxamine and tandospirone].

We experienced the first death case of the serotonin syndrome in Japan caused by fluvoxamine and tandospirone. A 15-year-old man was transported to our hospital for shock, muscle hypertonia and hyperthermia after cardiopulmonary arrest. His serum concentrations of fluvoxamine and tandospirone were 3,554 ng/mL and 698 ng/mL respectively after 24 hours from oral intake. He was dead in spite of intensive treatments. The progress of the serotonin syndrome is usually rapid. So, it should be monitored appropriately a patient with serotonin syndrome. If he has hyperthermia, immediate paralysis should be induced. We should aware of the serotonin syndrome a case of overdose on a serotonergic agent.