Presence Of Fluvoxamine Research Articles

A smartphone-based colorimetric assay using Au@Ag core–shell nanoparticles as the nanoprobes for visual tracing of fluvoxamine in biofluids as a common suicide drug

In the present study, bimetallic nanoparticles (NPs) consisting of gold (AuNPs) as the core and silver (AgNPs) as the shell have been synthesized and applied as the nanoprobe for detection of fluvoxamine (FXM) as the anti-depression drug. The physicochemical properties of the prepared citrate-capped Au@Ag core–shell NPs have been characterized by UV–Vis, Fourier-transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM) and scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDX) techniques. The design of the smartphone-based colorimetric FXM sensor relies on the fast hydrolysis of FXM under alkaline conditions by producing of 2-(Aminooxy)ethanamine without any significant peak at 400–700 nm. The interaction of the resulted molecule with the nanoprobe induced a red shift in the longitudinal localized surface plasmon resonance (LSPR) peak of the nanoprobe, which was accompanied by sharp and vivid color variations in the solution. A linear relationship between the absorption signal increasing by FXM concentration increasing from 1 µM to 10 µM presented a simple, low cost and minimally instrumented format for FXM quantification with a limit of detection (LOD) of 100 nM. The collected visual data with the elegant colorimetric response of the nanoprobe in the presence of FXM from Indian red to light red violet and bluish-purple color offered simple detection of FXM with the naked eye. The satisfactory results of the proposed cost-effective sensor in the rapid assay of FXM in human serum, urine, saliva and pharmaceutical samples guarantee the potential of the nanoprobe for on-site and visual determination of FXM in actual samples. The proposed sensor as the first non-invasive FXM sensor for saliva sample analysis may hold great promise to provide the technical support for the rapid and valid detection of FXM for forensic medicine and clinical organizations.

Duloxetine

Duloxetine, a potent reuptake inhibitor of serotonin (5-HT) and norepinephrine, is effective for the treatment of major depressive disorder, diabetic neuropathic pain, stress urinary incontinence, generalized anxiety disorder and fibromyalgia. Duloxetine achieves a maximum plasma concentration (C(max)) of approximately 47 ng/mL (40 mg twice-daily dosing) to 110 ng/mL (80 mg twice-daily dosing) approximately 6 hours after dosing. The elimination half-life of duloxetine is approximately 10-12 hours and the volume of distribution is approximately 1640 L. The goal of this paper is to provide a review of the literature on intrinsic and extrinsic factors that may impact the pharmacokinetics of duloxetine with a focus on concomitant medications and their clinical implications. Patient demographic characteristics found to influence the pharmacokinetics of duloxetine include sex, smoking status, age, ethnicity, cytochrome P450 (CYP) 2D6 genotype, hepatic function and renal function. Of these, only impaired hepatic function or severely impaired renal function warrant specific warnings or dose recommendations. Pharmacokinetic results from drug interaction studies show that activated charcoal decreases duloxetine exposure, and that CYP1A2 inhibition increases duloxetine exposure to a clinically significant degree. Specifically, following oral administration in the presence of fluvoxamine, the area under the plasma concentration-time curve and C(max) of duloxetine significantly increased by 460% (90% CI 359, 584) and 141% (90% CI 93, 200), respectively. In addition, smoking is associated with a 30% decrease in duloxetine concentration. The exposure of duloxetine with CYP2D6 inhibitors or in CYP2D6 poor metabolizers is increased to a lesser extent than that observed with CYP1A2 inhibition and does not require a dose adjustment. In addition, duloxetine increases the exposure of drugs that are metabolized by CYP2D6, but not CYP1A2. Pharmacodynamic study results indicate that duloxetine may enhance the effects of benzodiazepines, but not alcohol or warfarin. An increase in gastric pH produced by histamine H(2)-receptor antagonists or antacids did not impact the absorption of duloxetine. While duloxetine is generally well tolerated, it is important to be knowledgeable about the potential for pharmacokinetic interactions between duloxetine and drugs that inhibit CYP1A2 or drugs that are metabolized by CYP2D6 enzymes.

Electrochemical Quantification of Serotonin in the Live Embryonic Zebrafish Intestine

We monitored real-time in vivo levels of serotonin release in the digestive system of intact zebrafish embryos during early development (5 days postfertilization, dpf) using differential pulse voltammetry with implanted carbon fiber microelectrodes modified with carbon nanotubes dispersed in nafion. A detection limit of 1 nM, a linear range between 5 and 200 nM, and a sensitivity of 83.65 nA x microM(-1) were recorded. The microelectrodes were implanted at various locations in the intestine of zebrafish embryos. Serotonin levels of up to 29.9 (+/-1.13) nM were measured in vivo in normal physiological conditions. Measurements were performed in intact live embryos without additional perturbation beyond electrode insertion. The sensor was able to quantify pharmacological alterations in serotonin release and provide the longitudinal distribution of this neurotransmitter along the intestine with high spatial resolution. In the presence of fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), concentrations of 54.1 (+/-1.05) nM were recorded while in the presence of p-chloro-phenylalanine (PCPA), a tryptophan hydroxylase inhibitor, the serotonin levels decreased to 7.2 (+/-0.45) nM. The variation of serotonin levels was correlated with immunohistochemical analysis. We have demonstrated the first use of electrochemical microsensors for in vivo monitoring of intestinal serotonin levels in intact zebrafish embryos.

Selective serotonin re-uptake inhibitors decrease the cytokine-induced endothelial adhesion molecule expression, the endothelial adhesiveness to monocytes and the circulating levels of vascular adhesion molecules

BackgroundSelective serotonin reuptake inhibitors (SSRIs) exert cardioprotective effects. We examined whether SSRIs a) modulate endothelial cell expression of vascular cell adhesion molecule (VCAM-1), intracellular adhesion molecule (ICAM-1) and adhesiveness to U937 monocytes, b) reduce the circulating levels of these adhesion molecules in vivo. MethodsWe assessed the effect of SSRIs, (citalopram, fluvoxamine and fluoxetine), on TNF-alpha-induced expression of VCAM-1 and ICAM-1 in human aorta endothelial cells and adhesiveness to U937 monocytes. Cells were incubated with TNF-alpha in the absence and in the presence of SSRIs concentrations from 10−7 M to10−4 M and the VCAM-1 and ICAM-1 expression was quantified by cell-ELISA. The TNF-alpha-stimulated adhesiveness to U937 monocytes was also assessed. Twenty five patients with chronic heart failure and depression were randomized to receive sertaline 50 mg, p.o., o.d. (n=13) or placebo. At baseline and 3-months after treatment, we measured VCAM-1and ICAM-1 plasma levels. ResultsSSRIs decreased the TNF-alpha-induced endothelial expression of VCAM-1 at concentration range 10−7 M to 10−4 M (p<0.05). ICAM-1 expression was decreased in the presence of fluvoxamine and fluoxetine at concentrations from10−7 M to 10−4 M (p<0.05) and in the presence of citalopram at concentrations from 10−7 M to 10−5 M (p<0.05). All SSRIs inhibited the TNF-alpha-stimulated adhesiveness to U937 cells at 10−5 M and 10−4 M (p<0.05). Compared to baseline, there was a greater reduction in ICAM-1 and VCAM-1 levels post-sertaline than post placebo in heart failure patients (p<0.05). ConclusionSSRIs may exhibit an anti-inflammatory activity on endothelial cells and reduce circulating VCAM-1 and ICAM-1 in vivo, a mechanism which may partly mediate their cardioprotective effects.

In Vitro and In Vivo Evaluations of Cytochrome P450 1A2 Interactions with Duloxetine

To determine whether duloxetine is a substrate, inhibitor or inducer of cytochrome P450 (CYP) 1A2 enzyme, using in vitro and in vivo studies in humans. Human liver microsomes or cells with expressed CYP enzymes and specific CYP inhibitors were used to identify which CYP enzymes catalyse the initial oxidation steps in the metabolism of duloxetine. The potential of duloxetine to inhibit CYP1A2 activity was determined using incubations with human liver microsomes and phenacetin, the CYP1A2 substrate. The potential for duloxetine to induce CYP1A2 activity was determined using human primary hepatocytes treated with duloxetine for 72 hours. Studies in humans were conducted using fluvoxamine, a potent CYP1A2 inhibitor, and theophylline, a CYP1A2 substrate, as probes. The subjects were healthy men and women aged 18-65 years. Single-dose duloxetine was administered either intravenously as a 10-mg infusion over 30 minutes or orally as a 60-mg dose in the presence or absence of steady-state fluvoxamine (100 mg orally once daily). Single-dose theophylline was given as 30-minute intravenous infusions of aminophylline 250 mg in the presence or absence of steady-state duloxetine (60 mg orally twice daily). Plasma concentrations of duloxetine, its metabolites and theophylline were determined using liquid chromatography with tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods and evaluated using mixed-effects ANOVA. Safety measurements included vital signs, clinical laboratory tests, a physical examination, ECG readings and adverse event reports. The in vitro results indicated that duloxetine is metabolized by CYP1A2; however, duloxetine was predicted not to be an inhibitor or inducer of CYP1A2 in humans. Following oral administration in the presence of fluvoxamine, the duloxetine area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) and the maximum plasma drug concentration (C(max)) significantly increased by 460% (90% CI 359, 584) and 141% (90% CI 93, 200), respectively. In the presence of fluvoxamine, the oral bioavailability of duloxetine increased from 42.8% to 81.9%. In the presence of duloxetine, the theophylline AUC(infinity) and C(max) increased by only 13% (90% CI 7, 18) and 7% (90% CI 2, 14), respectively. Coadministration of duloxetine with fluvoxamine or theophylline did not result in any clinically important safety concerns, and these combinations were generally well tolerated. Duloxetine is metabolized primarily by CYP1A2; therefore, coadministration of duloxetine with potent CYP1A2 inhibitors should be avoided. Duloxetine does not seem to be a clinically significant inhibitor or inducer of CYP1A2; therefore, dose adjustment of CYP1A2 substrates may not be necessary when they are coadministered with duloxetine.

Fluvoxamine Affects Sildenafil Kinetics and Dynamics

Sildenafil used as oral drug treatment for erectile dysfunction is predominantly metabolized by the cytochrome P450 isozyme 3A4. The antidepressant fluvoxamine is an inhibitor of cytochrome P450 3A4. In a randomized, double-blind, placebo-controlled, crossover study, we evaluated the effects of fluvoxamine dosed to steady state on the pharmacokinetics and pharmacodynamics of sildenafil. Twelve healthy men received oral fluvoxamine or placebo for 10 days (50 mg every day on days 1-3; 100 mg every day on days 4-10). On day 11, all participants received a single, oral, open-label dose of 50 mg sildenafil, and blood samples were collected for analysis of sildenafil plasma concentrations by liquid chromatography/mass spectrometry. Concurrently, the effect of sildenafil on venodilation induced by a constant dose of sodium nitroprusside was assessed using the dorsal hand vein compliance technique. Sildenafil was well tolerated in the presence of fluvoxamine. During fluvoxamine, sildenafil exposure (area under the curve) significantly increased by 40% (P < 0.001), and its half-life increased by 19% (P = 0.034). Concurrently, sodium nitroprusside-induced venodilation was significantly augmented by 59% during fluvoxamine compared to placebo (P = 0.012). In conclusion, sildenafil kinetics are mildly affected by fluvoxamine which translates into an increase in vascular sildenafil effects. Whereas the pharmacokinetic changes do not suggest a large clinically relevant interaction, it may be prudent to consider a starting dose of 25 mg in patients concurrently treated with fluvoxamine.

Low-Dose Fluvoxamine as an Adjunct to Reduce Olanzapine Therapeutic Dose Requirements

Despite the advances in antipsychotic pharmacotherapy over the past decade, many atypical antipsychotic agents are not readily accessible by patients with major psychosis or in developing countries where the acquisition costs may be prohibitive. Olanzapine is an efficacious and widely prescribed atypical antipsychotic agent. In theory, olanzapine therapeutic dose requirement may be reduced during concurrent treatment with inhibitors of drug metabolism. In vitro studies suggest that smoking-inducible cytochrome P450 (CYP) 1A2 contributes to formation of the metabolite 4'-N-desmethylolanzapine. The present prospective study tested the hypothesis that olanzapine steady-state doses can be significantly decreased by coadministration of a low subclinical dose of fluvoxamine, a potent inhibitor of cytochrome P450 1A2. The study design followed a targeted "at-risk" population approach with a focus on smokers who were likely to exhibit increased cytochrome P450 1A2 expression. Patients with stable psychotic illness (N = 10 men, all smokers) and receiving chronic olanzapine treatment were evaluated for steady-state plasma concentrations of olanzapine and 4'-N-desmethylolanzapine. Subsequently, olanzapine dose was reduced from 17.5 +/- 4.2 mg/d (mean +/- SD) to 13.0 +/- 3.3 mg/d, and a nontherapeutic dose of fluvoxamine (25 mg/d, PO) was added to regimen. Patients were reevaluated at 2, 4, and 6 weeks during olanzapine-fluvoxamine cotreatment. There was no significant change in olanzapine plasma concentration, antipsychotic response, or metabolic indices (eg, serum glucose and lipids) after dose reduction in the presence of fluvoxamine (P > 0.05). 4'-N-desmethylolanzapine/olanzapine metabolic ratio decreased from 0.45 +/- 0.20 at baseline to 0.25 +/- 0.11 at week 6, suggesting inhibition of the cytochrome P450 1A2-mediated olanzapine 4'-N-demethylation by fluvoxamine (P < 0.05). In conclusion, this prospective pilot study suggests that a 26% reduction in olanzapine therapeutic dose requirement may be achieved by coadministration of a nontherapeutic oral dose of fluvoxamine.

Enantioselective disposition of lansoprazole in relation to CYP2C19 genotypes in the presence of fluvoxamine

Lansoprazole is affected by polymorphism of CYP2C19. The aim of this study was to examine the effects of fluvoxamine, a CYP2C19 inhibitor, on the pharmacokinetics of each lansoprazole enantiomer among three different CYP2C19 genotype groups. Eighteen healthy subjects, of whom six each were homozygous extensive metabolizers (homEMs), heterozygous extensive metabolizers (hetEMs), or poor metabolizers (PMs) for CYP2C19, participated in the study. Each subject received either placebo or fluvoxamine, 25 mg twice daily for 6 days, then a single oral dose of 60 mg of racemic lansoprazole. The plasma concentrations of lansoprazole enantiomers and lansoprazole sulphone were subsequently measured for 24 h post lansoprazole administration using liquid chromatography. In the homEMs and hetEMs, fluvoxamine significantly increased the AUC(0, infinity) and C(max) and prolonged the elimination half-life of both (R)- and (S)-lansoprazole, whereas in the PMs, the only statistically significant effect of fluvoxamine was on the AUC(0, infinity) for (R)-lansoprazole. The mean fluvoxamine-mediated percent increase in the AUC(0, infinity) of (R)-lansoprazole in the homEMs compared with the PMs was significant (P = 0.0117); however, C(max) did not differ among the three CYP2C19 genotypes. On the other hand, fluvoxamine induced a significant percent increase in both the AUC(0, infinity) and C(max) for (S)-lansoprazole in the homEMs compared with the hetEMs (P = 0.0007 and P = 0.0125, respectively) as well as compared with the PMs (P < 0.0001 for each parameter). The mean R : S ratio for AUC(0, infinity) of lansoprazole in the homEMs was significantly different between the placebo and the fluvoxamine treatment groups (12.7 (9.1, 16.8) vs 6.4 (5.4, 7.4), respectively, P < 0.0001), though not in the PMs (5.5 (4.3, 6.7) vs 5.9 (5.3, 6.5), respectively). The magnitude of the contribution of CYP2C19 to the metabolism of (S)-lansoprazole is much greater compared with that of the (R)-enantiomer. In extensive metabolizers, hepatic CYP2C19 plays an important role in the absorption and elimination of lansoprazole, particularly the (S)-enantiomer.

Role of extracellular serotonin levels in the effect of 5-HT1B receptor blockade.

The release of serotonin (5-HT) at serotonergic nerve terminals is regulated by 5-HT(1B) autoreceptors. Several studies have reported that the effects of selective 5-HT reuptake inhibitors (SSRIs) on extracellular 5-HT are augmented by 5-HT(1B) receptor antagonists, whereas administration of these antagonists alone do not enhance 5-HT levels. It has been suggested that 5-HT(1B) receptors have low basal endogenous activity and therefore elevated endogenous 5-HT levels are needed to elicit an effect of 5-HT(1B) receptor antagonists. To test this hypothesis, different strategies were used to enhance 5-HT levels in the rat frontal cortex to assess the effects of locally applied NAS-181, a new selective 5-HT(1B) receptor antagonist. Blockade of 5-HT(1B) receptors with NAS-181 dose dependently augmented 5-HT levels when 5-HT levels were enhanced by a SSRI. No additional effect of NAS-181 on 5-HT output was found when 5-HT levels were enhanced by KCl depolarization-induced release or by preventing degradation of 5-HT with the monoamine oxidase inhibitor pargyline. In the presence of fluvoxamine, the increased 5-HT release evoked by KCl depolarization was augmented by NAS-181, supporting the idea that blockade of 5-HT transporters is necessary to measure an effect of 5-HT(1B) receptor blockade. In conclusion, the results provide circumstantial evidence that the effect of a 5-HT(1B) receptor antagonist depends on extracellular 5-HT levels, but strongly suggest that additional 5-HT reuptake inhibition is required to detect any effect of 5-HT(1B) receptor antagonist on 5-HT levels by in vivo microdialysis.

5-Hydroxytryptamine-induced outward currents mediated via 5-HT(1A) receptors in neurons of the rat dorsolateral septal nucleus.

Effects of 5-hydroxytryptamine (5-HT) on neurons of the rat dorsolateral septal nucleus (DLSN) were examined by intracellular and whole-cell patch-clamp recording techniques. An outward current was induced by 5-HT (1-100 microM) in a concentration-dependent manner. The EC(50) for 5-HT was 4.8 microM. Also, 8-OH-DPAT (10-100 microM) produced the outward current an EC(50) of 17 microM. Amplitudes of the outward currents produced by 5-HT (100 microM) and 8-OH-DPAT (100 microM) were 117+/-4 (n=6) and 58+/-8 pA (n=6), respectively. Fluvoxamine (200 nM), a specific serotonin re-uptake inhibitor, enhanced the 5-HT (1 microM)-induced outward current: the EC(50) for 5-HT was 0.5 microM in the presence of fluvoxamine (200 nM). L-694247 (100 microM) and CP 93129 (100 microM) also produced outward currents with amplitudes of 33+/-3 (n=4) and 18+/-5 pA (n=4), respectively in DLSN neurons. DOI (100 microM) and RS 67333 (100 microM) did not produce outward currents. NAN-190 shifted, in a parallel manner, the concentration-response relationship of 5-HT to the right. The Lineweaver-Burk plot of the concentration-response curve showed that NAN-190 depressed the 5-HT-induced current in a competitive manner. The current-voltage relationship indicates that the 5-HT-induced current reversed polarity at a potential close to the equilibrium potential of K(+). Ba(2+) (100 microM-1 mM) partially depressed the outward current produced by 5-HT. These results suggest that 5-HT induces multiple K(+) currents via 5-HT(1A) receptors in DLSN neurons.

Serotonin uptake blockers influence serotonin autoreceptors by increasing the biophase concentration of serotonin and not through a ?molecular link?

The mechanism of the attenuation, by serotonin uptake blockers, of the release-inhibiting effect of exogenous serotonin autoreceptor agonists was studied in rabbit brain cortex and rat hypothalamus slices. The slices were preincubated with 3H-serotonin and then superfused and stimulated electrically. In rabbit brain slices stimulated by trains of 4 pulses at 100 Hz, 5-carboxamidotryptamine and 5-methoxytryptamine reduced the evoked overflow of tritium, and their concentration-response curves were not changed by any of three serotonin uptake inhibitors, namely citalopram, fluvoxamine and 6-nitroquipazine. In contrast, when the slices were stimulated by trains of 10 pulses at 0.033 Hz, fluvoxamine shifted the concentration-response curve of 5-methoxytryptamine to the right. Experiments with the autoreceptor antagonist metitepine indicated that little, if any, endogenous autoinhibitory tone developed in the course of trains of 4 pulses/100 Hz, irrespective of the absence or presence of uptake inhibitors, as well as during trains of 10 pulses/0.033 Hz in the absence of uptake inhibitors, whereas marked autoinhibition developed when 10 pulses/0.033 Hz were applied in the presence of fluvoxamine. In rat hypothalamic slices stimulated by trains of 4 pulses at 100 Hz, citalopram also failed to change the concentration-response curve of 5-methoxytryptamine. These results indicate that serotonin uptake blockers attenuate the effect of exogenous autoreceptor agonists by an increase in the biophase concentration of released serotonin and, hence, in endogenous autoinhibitory tone, and not by some direct "molecular link" unrelated to the biophase concentration of released serotonin.