A fluvoxamine-related fatality: Case report with postmortem concentrations.

Fluvoxamine is a selective serotonin reuptake inhibitor that has been considered relatively safe in overdose. At therapeutic and supratherapeutic concentrations, fluvoxamine affects cardiac conduction, prolongs QTc interval, causes hypotension, obtundation, and can increase propensity for seizures. A man in his 60s was found dead at his home with a postmortem fluvoxamine peripheral blood concentration of 4.9 mg/L, and a liver concentration of 440 mg/kg. His cause of death was determined to be acute fluvoxamine toxicity.

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.

Sensitive and selective determination of fluvoxamine maleate using a sensitive chemiluminescence system based on the alkaline permanganate-Rhodamine B-gold nanoparticles reaction.

A high-yield chemiluminescence (CL) system based on the alkaline permanganate-Rhodamine B reaction was developed for the sensitive determination of fluvoxamine maleate (Flu). Rhodamine B is oxidized by alkaline KMnO4 and a weak CL emission is produced. It was demonstrated that gold nanoparticles greatly enhance this CL emission due to their interaction with Rhodamine B molecules. It is also observed that sodium dodecyl sulfate, an anionic surfactant, can strongly increase this enhancement. In addition, it was demonstrated that a notable decrease in the CL intensity is observed in the presence of Flu. This may be related to Flu oxidation with KMnO4 . There is a linear relationship between the decrease in CL intensity and the Flu concentration over a range of 2-300 µg/L. A new simple, rapid and sensitive CL method was developed for the determination of Flu with a detection limit (3s) of 1.35 µg/L. The proposed method was used for the determination of Flu in pharmaceutical and urine samples.

Synthesis and characterization of poly[N-isopropylacrylamide-co-1-(N,N-bis-carboxymethyl)amino-3-allylglycerol] grafted to magnetic nano-particles for the extraction and determination of fluvoxamine in biological and pharmaceutical samples.

In this research, a novel method is reported for the surface grafting of N-isopropylacrylamide as a thermosensitive agent and 1-(N,N-bis-carboxymethyl)amino-3-allylglycerol with an affinity toward fluvoxamine onto magnetic nano-particles modified by 3-mercaptopropyltrimethoxysilane. The grafted nano-particles were characterized by Fourier transform infrared spectroscopy, elemental analysis, and thermogravimetric analysis. The surface morphology was studied with scanning electron microscopy and transmission electron microscopy. The resulting grafted nano-particles were used in solid phase extraction and determining of trace fluvoxamine in biological human fluids and pharmaceutical samples. The profile of the fluvoxamine uptake by the modified magnetic nano-particles indicated good accessibility of the active sites in the grafted copolymer. It was found that the adsorption behavior could be fitted by the Freundlich adsorption isotherm model. It was observed that a maximum amount of fluvoxamine was released at a temperature above the lower critical solution temperature of the polymer.

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.

Spectrofluorimetric determination of fluvoxamine in dosage forms and plasma via derivatization with 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole.

A highly sensitive and simple spectrofluorimetric method has been developed and validated for the determination of the antidepressant fluvoxamine (FXM) in its dosage forms and plasma. The method was based on nucleophilic substitution reaction of FXM with 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole in an alkaline medium (pH 8) to form a highly fluorescent derivative that was measured at 535 nm after excitation at 470 nm. The factors affecting the reaction was carefully studied and optimized. The kinetics of the reaction was investigated, and the reaction mechanism was presented. Under the optimized conditions, linear relationship with good correlation coefficient (0.9995) was found between the fluorescence intensity and FXM concentration in the range of 65-800 ng ml(-1). The limits of detection and quantitation for the method were 21 and 64 ng ml(-1), respectively. The precision of the method was satisfactory; the values of relative standard deviations did not exceed 2.17%. The proposed method was successfully applied to the determination of FXM in its pharmaceutical tablets with good accuracy; the recovery values were 97.8-101.4 +/- 1.08-2.75%. The results obtained by the proposed method were comparable with those obtained by the official method. The high sensitivity of the method allowed its successful application to the analysis of FXM in spiked human plasma. The proposed method is superior to the previously reported spectrofluorimetric method for determination of FXM in terms of its simplicity. The proposed method is practical and valuable for its routine application in quality control and clinical laboratories for analysis of FXM.

Quality assessment of fluoxetine and fluvoxamine pharmaceutical formulations purchased in different countries or via the Internet by 19F and 2D DOSY 1H NMR.

A simple and selective (19)F NMR method has been validated for the quantitation of fluoxetine (FLX) and fluvoxamine (FLV) in methanol solutions and in human plasma and urine. The regression equations for FLX and FLV showed a good linearity in the range of 1.4-620 microg mL(-1) (3.3 x 10(-6)-1.8 x 10(-3) mol L(-1)) with a limit of detection of approximately 0.5 microg mL(-1) (1.3 x 10(-6) mol L(-1)) and a limit of quantification of approximately 2 microg mL(-1) (4.6 x 10(-6) mol L(-1)). The precision of the assay depends on the concentrations and is comprised between 1.5 and 9.5% for a range of concentrations between 1.2 x 10(-3) and 3.2 x 10(-6) mol L(-1). The accuracy evaluated through recovery studies ranged from approximately 96 to 103% in methanol solutions and in urine, and from approximately 93 to 104% in plasma, with standard deviations <7.5%. The low sensitivity of the method precludes its use for the assay of these antidepressants in biofluids at least at therapeutic doses as the ranges of FLX and FLV plasma levels are 0.15-0.5 microg mL(-1) and 0.15-0.25 microg mL(-1), respectively. The method was applied successfully to the determination of FLX and FLV contents in pharmaceutical samples (brand-named and generic) purchased in several countries or via the Internet. All the commercial formulations contain the active ingredient in the range 94-103% of stated concentration. A "signature" of the formulations (solid and liquid) was obtained with 2D Diffusion-Ordered SpectroscopY (DOSY) (1)H NMR which allowed the characterisation of the active ingredient and excipients present in the formulations studied. Finally, the DOSY separation of FLX and FLV whose molecular weights are very close was obtained by using beta-cyclodextrin as host-guest complexing agent.

Spectrofluorometric determination of fluvoxamine in dosage forms, spiked plasma, and real human plasma by derivatization with fluorescamine.

A sensitive, simple, and selective spectrofluorometric method was developed for the determination of fluvoxamine (FXM) in pharmaceutical formulations and biological fluids. The method is based upon the reaction between the drug and fluorescamine in borate buffer of pH 8.0 to yield a highly fluorescent derivative that is measured at 481 nm after excitation at 383 nm. The different experimental parameters affecting the development and stability of the reaction product were carefully studied and optimized. The method was applied for the determination of the drug over the concentration range of 0.1-1.1 microg/mL with a detection limit of 0.01 microg/mL (2 x 10(-8) M). The proposed method was successfully applied to the analysis of commercial tablets. The results obtained were in good agreement with those obtained using a reported spectrophotometric method. The method was applied for the determination of FXM in spiked human plasma with recovery (n=4) of 97.32 +/- 1.23%, while that in real human plasma (n=3) was 90.79 +/- 2.73%. A proposal for the reaction pathway is presented.

Selective serotonin reuptake inhibitors in sewage influents and effluents from Tromsø, Norway.

An analytical method for quantification of the selective serotonin reuptake inhibitors (SSRIs) citalopram, sertraline, paroxetine, fluoxetine and fluvoxamine in sewage influents and effluents from selected sewage treatment plants (STPs) has been developed and validated. This quantification method is based on solid phase extraction of 2.5L samples, followed by liquid-liquid extraction for further sample clean up in order to minimize matrix effects during subsequent quantification. The samples were analysed on a high performance liquid chromatograph coupled to a triple quadrupole mass spectrometric detector using 0.1% ammonia in acetonitrile/water as mobile phase, with positive electrospray ionisation and multiple reaction monitoring for detection and quantification. 1-[3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)propyl]-pyrrolidine (N-7084) was used as internal standard for quantification. The recovery rates of the SSRIs ranged between 54 and 84%, and the method limit of quantification (MLQ) was between 120 and 290 pg/L for the target compounds. Samples were collected in July 2005 from three different STPs and a pump station in Tromsø, Northern Norway. Two of the STPs serve the University hospital and its psychiatric department, respectively, in addition to domestic sewage. SSRIs were detected in all samples collected. The concentrations varied greatly from below the MLQ to several hundreds ng/L. Concentrations in influents were higher compared to filtered effluents, indicating that SSRIs adsorb to particulate matter, are degraded by microorganisms, or degraded in other ways during the filtration process. However, more samples should be analysed before general conclusions can be drawn.

Exposure assessment and microcosm fate of selected selective serotonin reuptake inhibitors.

The exposure and fate of selective serotonin reuptake inhibitors (SSRIs) was evaluated using modeled predicted environmental concentrations (PECs) according to the U.S. and the European Union (EU) guidelines and microcosm model ecosystems. According to the U.S. guidance, crude environmental introduction concentrations, the only SSRI that would require environmental assessment would be sertraline. However, the more conservative EU draft guidance PEC would require further assessment of all five SSRIs. Refined PECs developed using the U.S. and the EU guidelines along with estimates of removal by sewage treatment and receiving water dilution factors indicate that the U.S. methodology corresponds better to MEC data determined in the U.S. and Canada. Worst-case (99th centile) PECs for citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline were 30, 19, 30, 65, and 122 ng/L, respectively, using the U.S. methodology and 142, 182, 841, 144, and 575 ng/L, respectively, using the EU draft methodology. The dissipation of fluoxetine and fluvoxamine from the water column in aquatic microcosms was best described using a two-compartment model while sertraline followed a one-compartment model. Fluoxetine and fluvoxamine water concentrations initially dissipated with first phase half-lives of 3.8 and 1.8 days, respectively, but levelled off at concentrations around 10 microg/L with second phase half-lives of 76.7 and 59.3 days, respectively, not including those estimated as infinity. Sertraline dissipation tended toward the detection limit with a half-life of 3.4 days. Fluoxetine was found to be the most persistent followed by fluvoxamine and sertraline. Estimated log(K(OC)) values for all SSRIs were >4.3 indicating that SSRIs are expected to adsorb to sediment or sludge. Partitioning into other environmental compartments such as this may act as a reservoir from which SSRIs may be re-released into surface waters and indicates the potential susceptibility of benthos.

Electroanalytical study of fluvoxamine.

Fluvoxamine (FVX) can be reduced at a mercury-drop electrode, with a maximum peak current intensity being obtained at a potential of -0.7 V vs. Ag/AgCl, in an aqueous electrolyte solution of pH 2. The compound was determined in a pharmaceutical product and in spiked human serum by square-wave adsorptive-stripping voltammetry (SWAdSV) after accumulation at the electrode surface, under batch conditions. Because the presence of dissolved oxygen did not interfere significantly with the analysis, it was also possible to determine FVX in the pharmaceutical product by use of a flow-injection analysis (FIA) system with SWAdSV detection. The methods developed were validated and successfully applied to the quantification of FVX in a pharmaceutical product. Recoveries between 76 and 89% were obtained in serum analysis. The FIA-SWAdSV method enabled analysis of up to 120 samples per hour at reduced cost, implying the possibility of competing with the chromatographic methods usually used for this analysis.

Photo-isomerization of fluvoxamine in aqueous solutions.

The hydrolysis and photolysis of fluvoxamine, a selective serotonin reuptake inhibitor, in aqueous buffer solutions (pH 5, 7, and 9), in synthetic humic water, and lake waters were investigated in the dark and in a growth chamber outfitted with fluorescent lamps simulating the UV output of sunlight at 25 degrees C. No significant hydrolytic degradation/isomerization was observed for 30 days in all aqueous solutions. However, fluvoxamine was moderately isomerized to its (Z)-isomer by simulated sunlight. The photo-isomerization occurred in two stages. The photo-isomerization occurred rapidly within the first 7 days and slowly thereafter with a rate constant of 0.12-0.19 day(-1) for the first stage and 0.04-0.05 day(-1) for the second stage. Photosensitized rate constants in synthetic humic water and in lake waters were approximately 6-7 times faster than that in pH 9 buffer with the rate constants of 1.15-1.34 day(-1) in the first stage. The (Z)-isomer of fluvoxamine was the only product detected in all aqueous solutions and was identified using LC-ESI-MS.

Determination of fluvoxamine and its metabolite fluvoxamino acid by liquid-liquid extraction and column-switching high-performance liquid chromatography.

This study describes a new simultaneous determination of fluvoxamine and fluvoxamino acid by automated column-switching high-performance liquid chromatography. The test compounds were extracted from 1.5 ml of plasma using chloroform-toluene (15:85, v/v), and the extract was injected into a hydrophilic metaacrylate polymer column for clean-up and a C18 analytical column for separation. The mobile phase for separation consisted of phosphate buffer (0.02 M, pH 4.6), acetonitrile and perchloric acid (60%) (62.4:37.5:0.1, v/v/v) and was delivered at a flow rate of 0.6 ml/min. The peak was detected using a UV detector set at 254 nm. The method was validated for the concentration range 0.8-153.6 ng/ml for fluvoxamine and 0.6-115.2 ng/ml for fluvoxamino acid, and their good linearity (r > 0.998) were confirmed. Intra-day coefficient variations (CVs) for fluvoxamine and fluvoxamino acid were less than 6.6 and 6.0%, respectively. Inter-day CVs for corresponding compounds were 6.3 and 6.5%, respectively. Relative errors ranged from -18 to 9% and mean recoveries were 96-100%. The limit of quantification was 1.2 and 0.9 ng/ml for fluvoxamine and fluvoxamino acid, respectively. This method shows successful application for pharmacokinetic studies and therapeutic drug monitoring.

Study and analytical application of ion-pair formation in the system fluoxetine-pyrocatechol violet and fluvoxamine-pyrocatechol violet.

Pyrocatechol violet (PCV) reacts in aqueous media with fluoxetine (FLX) and fluvoxamine (FLV) forming coloured ion-association complexes, which are insoluble in water but quantitatively extracted into chloroform-n-butanol mixture. The composition of the compounds, studied by spectrophotometric methods showed that the molar ratio PCV : FLX and PCV : FLV is 1 : 1. The compounds were characterized by UV-VIS, IR and NMR spectrometry. Under optimal experimental conditions fluoxetine and fluvoxamine were determined in the range 1.3-18.0 microg/ml and 2.6-39.1 microg/ml, respectively. The proposed methods have been succesfully applied to the determination of these drugs in pharmaceuticals and natural samples.

The amount of fluvoxamine in milk is unlikely to be a cause of adverse effects in breastfed infants.

The aim of this study was to characterize milk/plasma (M/P) ratio, as well as relative infant dose and well-being, in 2 breastfeeding women taking fluvoxamine. The women (37 and 34 years old) and their infants (26 and 0.75 months old) were studied over a 24-hour dose interval at steady state. Fluvoxamine concentrations were measured by high-performance liquid chromatography. Infant exposure was measured as concentration in milk multiplied by an estimated milk production of 0.15 L/kg/d and normalized to the weight-adjusted maternal dose. M/P values of 1.34 and 1.21 were calculated for subjects 1 and 2, respectively, and relative infant doses were estimated to be 1.38% and 0.8%, respectively. No adverse effects in the infants were detected by the mother or on clinical examination, and fluvoxamine was not detected in the infants' plasma (limit of detection 2 micrograms/L). These limited data support the prescription of fluvoxamine to breastfeeding mothers after a careful, individual risk/benefit analysis is undertaken.

Fluorine magnetic resonance spectroscopy measurement of brain fluvoxamine and fluoxetine in pediatric patients treated for pervasive developmental disorders.

OBJECTIVE: Pediatric populations, including those with autistic disorder or other pervasive developmental disorders, increasingly are being prescribed selective serotonin reuptake inhibitors (SSRIs). Little is known about the age-related brain pharmacokinetics of SSRIs; there is a lack of data regarding optimal dosing of medications for children. The authors used fluorine magnetic resonance spectroscopy ((19)F MRS) to evaluate age effects on whole-brain concentrations of fluvoxamine and fluoxetine in children taking SSRIs. METHOD: Twenty-one pediatric subjects with diagnoses of autistic disorder or other pervasive developmental disorders, 6-15 years old and stabilized with a consistent dose of fluvoxamine or fluoxetine, were recruited for the study; 16 successfully completed the imaging protocol. Whole-brain drug levels in this group were compared to similarly acquired data from 28 adults. RESULTS: A significant relationship between dose and brain drug concentration was observed for both drugs across the age range studied. Brain fluvoxamine concentration in the children was lower, consistent with a lower dose/body mass drug prescription; when brain concentration was adjusted for dose/mass, age effects were no longer significant. Brain fluoxetine concentration was similar between age groups; no significant age effects on brain fluoxetine drug levels remained after adjustment for dose/mass. Observations of brain fluoxetine bioavailability and elimination half-life also were similar between age groups. CONCLUSIONS: These findings suggest that fluvoxamine or fluoxetine prescriptions adjusted for dose/mass are an acceptable treatment approach for medicating children with autistic disorder or other pervasive developmental disorders. It must be determined whether these findings can be generalized to other pediatric populations.

Determination of moclobemide, paroxetine, and fluvoxamine in tablets by HPLC.

A simple, accurate high performance liquid chromatography procedure is presented in order to determine moclobemide in Aurorix-tablets, paroxetine in Seroxat-tablets and fluvoxamine in Fevarin tablets. These drugs were chromatographed on a Nova-Pak C18, (dp = 4 microm), 150x3.9 mm i.d. column using methanol/phosphate butter adjusted to pH 2.65 with phosphoric acid (7:3, v/v) as the mobile phase to determining of the moclobemide and methanol/tetrahydrofuran/phosphate buffer at pH 2.65 (53:5:4, v/v) for determining of paroxetine and fluvoxamine. The detection was carried at 235 nm. The method was tested for linearity over the range 5-50 microg/ml. The relative standard deviation for moclobemide is 1.16, but for paroxetine and fluvoxamine is less than 1% (0.25 and 0.46 respectively).

[The transfer of selective serotonin reuptake inhibitors to human milk]. / Overgang av selektive serotoninreopptakshemmere til morsmelk.

BACKGROUND: This article presents an overview of the excretion of the SSRIs citalopram, paroxetine, fluoxetine, fluvoxamine and sertraline in breast milk. MATERIAL AND METHODS: Published articles on selective serotonin reuptake inhibitors and excretion in breast milk were identified and reviewed. In addition, drug concentrations were measured in milk from eight women using paroxetine (n = 4), citalopram (n = 3) or fluvoxamine (n = 1). RESULTS: Data from the literature indicate that the relative dose to the infant is lowest for fluvoxamine and sertraline, somewhat higher for paroxetine and highest for citalopram and fluoxetine. Adverse effects were reported in three of the 119 breastfed infants. Our own results show minimal excretion of fluvoxamine, small excretion of paroxetine and higher excretion of citalopram into breast milk. INTERPRETATION: If treatment with a selective serotonin reuptake inhibitor is started during the postpartum period, fluoxetine should not be the first alternative. High doses of citalopram should also be used with caution. However, when the use of an SSRI is clearly indicated in a breastfeeding woman, available data generally indicate that the positive effects of breast-feeding outweigh the risks for pharmacological effects in the infant.

Serum fluvoxamine levels in breastfed infants.

BACKGROUND: Between 10% and 15% of new mothers will experience an episode of postpartum depression. Although antidepressants are effective agents for the treatment of postpartum depression, minimal data are available to support their safety in infants of breastfeeding mothers. METHOD: In this article, we present 2 cases of nursing mother-infant pairs in which the mother was treated with fluvoxamine and in which infant serum fluvoxamine levels were obtained. Both mothers began the fluvoxamine treatment postpartum, and serum levels were obtained from mothers and infants after a minimum of 7 days on a stable maternal dose. One level was obtained from the infant in case 1, and 2 levels were obtained from the infant in case 2. RESULTS: Each of the infant serum fluvoxamine levels obtained was too low to quantify (at a limit of detection of 2.5 ng/mL). Neither of the infants experienced adverse events related to the mother's treatment with fluvoxamine. Each of the infants is reportedly healthy 2 to 3 years after the exposure. CONCLUSION: While these results are encouraging, they are limited and cannot be generalized to all cases of infants exposed to fluvoxamine. Additional mother-infant serum fluvoxamine levels and infant behavioral observations will facilitate the risk-benefit decision-making process for women who choose to breast-feed while taking fluvoxamine.

Alleviation of sleep disturbance and repetitive behavior by a selective serotonin re-uptake inhibitor in a boy with Asperger's syndrome.

An 8 year-old boy with Asperger's syndrome had difficulties in communicating with his teachers and classmates. He occasionally stole out of the classroom. He could not sleep at night recalling his awful experience and kept crying every night and refused to go to school. The treatment with fluvoxamine was started at the dose of 25 mg daily. Four weeks after the treatment, his repetitive behavior and hyperactivity decreased and night crying diminished. Although he still has difficulties in communicating with others, he is now able to attend extra-curricular classes in a private school. Fluvoxamine, a selective serotonin re-uptake inhibitor that has been mainly used for patients with depression and obsessive-compulsive disorder, might be effective for compulsive symptoms and sleep disturbance of patients with pervasive developmental disorders.