Fluvoxamine Research Articles

開眼失行を呈した筋萎縮性側索硬化症／前頭側頭葉変性症の１例

We report the case of a 76-year-old man with apraxia of eyelid opening (AEO) and amyotrophic lateral sclerosis with dementia (ALS-D)/frontotemporal lobar degeneration with motor neuron disease (FTLD-MND). The initial symptom was AEO. Neurological examination revealed mainly bulbar symptoms with a neurogenic pattern on needle electromyograms of the tongue muscles and the biceps muscles. Furthermore, he developed severe dementia with frontal lobe dysfunction and progressive non-fluent aphasia. Brain magnetic resonance imaging revealed severe cerebral atrophy and leukoaraiosis in the bilateral frontal lobes and the anterior part of the bilateral temporal lobes; brain 99mTc ethyl cysteinate dimer single photon emission computed tomography (ECD SPECT) showed hypoperfusion in the same areas. The patient showed improvement in stereotyped behavior and AEO after treatment with 50 mg/day of fluvoxamine maleate (the initial dose was 25 mg/day). Because serotonin receptors are markedly reduced in the frontal and temporal cortexes of patients with FTLD, we considered that dysfunction of the serotonergic system in the frontotemporal lobe caused AEO. Considering the findings of this case along with those of previous reports, we propose that there is a relatively homogeneous development of ALS-D/FTLD-MND with AEO.

Fluvoxamine and sigma-1 receptor agonists dehydroepiandrosterone (DHEA)-sulfate induces the Ser 473-phosphorylation of Akt-1 in PC12 cells

Aims The expression of brain-derived neurotrophic factor (BDNF) may be a downstream target of a variety of antidepressant treatments, and selective serotonin reuptake inhibitors (SSRIs) are used clinically for the treatment of depression. BDNF binds to and activates tyrosine kinases receptor (TrkB) to exert its effects. TrkB, after activation by ligands, stimulates phosphoinositide 3-kinase (PI3K). The downstream target of PI3K is Akt-1, a serine-threonine kinase. BDNF has signaling through the PLC-IP 3/Ca 2+ pathway. Furthermore, the PLC-γ/IP 3/Ca 2+ pathway is regulated by the sigma-1 receptors. Here, we examined whether fluvoxamine (FLV) activated Akt-1 and increased phosphorylation of Akt-1 via sigma-1 receptor in PC12 cells. Main methods We examined the effect of the SSRI, FLV and BDNF on the phosphorylation levels of serine-threonine kinase Akt-1 in PC12 cells using immunoblotting techniques. Key findings Treatment with 10 μM and 100 μM FLV of PC12 cells stimulated a 2.4- and 3.8-fold maximal increase in Ser 473-phosphorylated Akt-1 levels at 40 min, respectively. Treatment with 50 ng/ml BDNF also stimulated Ser 473 -phosphorylated Akt-1 by 2.6-fold with a maximal increase at 5 min. In addition, the phosphorylation induced by FLV and BDNF was blocked by LY294002, a selective inhibitor of PI3K. The sigma-1 receptor agonists dehydroepiandrosterone (DHEA)-sulfate also stimulated a 2.1-fold increase in the level of Ser473-phosphorylated Akt-1. Significance This study demonstrates that fluvoxamine treatment rapidly increased phosphorylation of Akt-1. And BDNF activated Akt-1 phosphorylation by the TrkB/PI3K/Akt-1 pathway. We conclude that the phosphorylation of Akt-1, downstream of PI3K, was the key to their antidepressant effects.

Intractable depression successfully treated with a combination of autogenic training and high-dose antidepressant in department of otorhinolaryngology: a case report.

Patients suffering from ear discomfort are commonly encountered in the department of otolaryngology. If various clinical examinations do not reveal any objective findings, then the patients are referred to the department of internal medicine or psychiatry. Psychotherapy is recommended in some cases. This paper describes the successful administration of autogenic training in a patient suffering from ear discomfort due to major depression. We present a case of intractable depression that was successfully treated with a combination of psychotherapy, administered by a clinical psychologist, and high-dose antidepressant. The patient was a 36-year-old female with hearing discomfort in her left ear. In 2003, she experienced insomnia and an appetite loss, and her condition was diagnosed as major depression along with an avoidant personality disorder. Her depression has not been improved with antidepressant treatment for 3 years in department of psychosomatic medicine. She was referred to our department because of ear discomfort in her left ear. There was no abnormality in her physical examinations. She wanted to be treated in department of otorhinolaryngology. We increased the dose of fluvoxamine maleate up to 200 mg/day, and introduced cognitive therapy and autogenic training by a clinical psychologist. Eventually, her depressive state as well as the hearing complaint was markedly alleviated. Autogenic training can be a viable and acceptable treatment option for patients who fail to respond to other therapies. This case emphasizes the importance of autogenic training as a method to control physical symptom of depression.

Management of obsessive-compulsive disorder with fluvoxamine extended release

The pharmacodynamic properties of fluvoxamine maleate include the modulation of different populations of serotonergic, dopaminergic, and sigma receptors and/or transporters, a complex pattern of activity that may account for its efficacy in the treatment of obsessive-compulsive disorder (OCD). Nevertheless, its pharmacokinetic profile and its pattern of side effects may hinder a rapid dose escalation, a therapeutic strategy that might be utterly desirable in patients with OCD. In preclinical studies, the maximum plasma concentration and bioavailability of an extended-release (CR) formulation of fluvoxamine were, respectively, 38% and 16% lower than those of the standard (ie, non-CR) formulation. Recently, the US Food and Drug Administration approved the fluvoxamine CR formulation for the treatment of OCD in adults. This approval was based on the results of a double-blind, placebo-controlled study with 253 OCD patients in which fluvoxamine CR showed a consistently earlier onset of therapeutic effects than other selective serotonin reuptake inhibitors, as reported in previous studies. The use of the CR formulation of fluvoxamine allowed a particularly aggressive dosing strategy at the beginning of the titration phase, ie, treatment could be started with a single dose of fluvoxamine CR 100 mg at bedtime, while keeping the occurrence of side effects and the rate of compliance at levels comparable to those reported for the use of immediate-release fluvoxamine.

Effect of smoking and CYP2D6 polymorphisms on the extent of fluvoxamine–alprazolam interaction in patients with psychosomatic disease

Fluvoxamine (FVX) is metabolized by cytochrome P450 (CYP) 2D6 and CYP1A2 and inhibits CYP3A4. The aim of this study was to investigate the factors responsible for interindividual variability in the extent of interaction between FVX and alprazolam (ALP). Blood samples were taken from 49 depressive patients to determine plasma concentration of FVX, ALP or both. Twenty-four samples were taken during the FVX-alone period, 21 samples during the ALP-alone period and 30 samples during the FVX-ALP period. Subjects were also genotyped for CYP2D6. The concentration-to-dose (C/D) ratio of ALP during the FVX-treatment period was significantly higher than that during the ALP-alone period. The CYP2D6 genotype affected neither the C/D ratios of FVX nor the extent of interaction. The mean C/D ratio of FVX in smokers was reduced by more than 30% in comparison with that in non-smokers. The mean C/D ratio of ALP in non-smokers was increased by FVX, while that in smokers was unchanged. The extent of interaction between FVX and ALP may be affected by smoking, which alters the C/D ratio of FVX. Therefore, when FVX and ALP are concomitantly administered, it should be noted that non-smokers may exhibit greater drug interaction than smokers.

Intractable depression successfully treated with a combination of autogenic training and high-dose antidepressant in department of otorhinolaryngology: a case report

IntroductionPatients suffering from ear discomfort are commonly encountered in the department of otolaryngology. If various clinical examinations do not reveal any objective findings, then the patients are referred to the department of internal medicine or psychiatry. Psychotherapy is recommended in some cases. This paper describes the successful administration of autogenic training in a patient suffering from ear discomfort due to major depression.Case presentationWe present a case of intractable depression that was successfully treated with a combination of psychotherapy, administered by a clinical psychologist, and high-dose antidepressant. The patient was a 36-year-old female with hearing discomfort in her left ear. In 2003, she experienced insomnia and an appetite loss, and her condition was diagnosed as major depression along with an avoidant personality disorder. Her depression has not been improved with antidepressant treatment for 3 years in department of psychosomatic medicine. She was referred to our department because of ear discomfort in her left ear. There was no abnormality in her physical examinations. She wanted to be treated in department of otorhinolaryngology. We increased the dose of fluvoxamine maleate up to 200 mg/day, and introduced cognitive therapy and autogenic training by a clinical psychologist. Eventually, her depressive state as well as the hearing complaint was markedly alleviated.ConclusionAutogenic training can be a viable and acceptable treatment option for patients who fail to respond to other therapies. This case emphasizes the importance of autogenic training as a method to control physical symptom of depression.

Spectrophotometric study for the reaction between fluvoxamine and 1,2-naphthoquinone-4-sulphonate: Kinetic, mechanism and use for determination of fluvoxamine in its dosage forms

Spectrophotometric study was carried out, for the first time, to investigate the reaction between the antidepressant fluvoxamine (FXM) and 1,2-naphthoquinone-4-sulphonate (NQS) reagent. In alkaline medium (pH 9), an orange-colored product exhibiting maximum absorption peak ( λ max) at 470 nm was produced. The kinetics of the reaction was investigated and its activation energy was found to be 2.65 kcal mol −1. Because of this low activation energy, the reaction proceeded easily. The stoichiometry of the reaction was determined and the reaction mechanism was postulated. This color-developing reaction was successfully employed in the development of simple and rapid spectrophotometric method for determination of FXM in its pharmaceutical dosage forms. Under the optimized reaction conditions, Beer's law correlating the absorbance ( A) with FXM concentration ( C) was obeyed in the range of 0.6–8 μg ml −1. The regression equation for the calibration data was A = 0.0086 + 0.1348 C, with good correlation coefficient (0.9996). The molar absorptivity ( ɛ) was 5.9 × 10 4 l mol −1 cm −1. The limits of detection and quantification were 0.2 and 0.6 μg ml −1, respectively. The precision of the method was satisfactory; the values of relative standard deviations did not exceed 2%. The proposed method was successfully applied to the determination of FXM in its pharmaceutical tablets with good accuracy and precisions; the label claim percentage was 100.47 ± 0.96%. The results obtained by the proposed method were comparable with those obtained by the official method. The proposed method is superior to all the previously reported spectrophotometric methods for determination of FXM in terms of its simplicity and sensitivity. The method is practical and valuable for its routine application in quality control laboratories for analysis of FXM.

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.

T1393 Fluvoxamine Versus Amitryptiline in Females with IBS and Depression

T1393 Fluvoxamine Versus Amitryptiline in Females with IBS and Depression

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 19F 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 μg mL −1 (3.3 × 10 −6–1.8 × 10 −3 mol L −1) with a limit of detection of ≈0.5 μg mL −1 (1.3 × 10 −6 mol L −1) and a limit of quantification of ≈2 μg mL −1 (4.6 × 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 × 10 −3 and 3.2 × 10 −6 mol L −1. The accuracy evaluated through recovery studies ranged from ≈96 to 103% in methanol solutions and in urine, and from ≈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 μg mL −1 and 0.15–0.25 μg 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) 1H 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 β-cyclodextrin as host–guest complexing agent.

Dose-Dependent Effects of the 3435 C&gt;T Genotype of ABCB1 Gene on the Steady-State Plasma Concentration of Fluvoxamine in Psychiatric Patients

This study investigated effects of the 3435 C>T genotype of the adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1, MDR1) gene on the steady-state plasma concentration of fluvoxamine (FLV). Sixty-two psychiatric patients were treated with different doses (50, 100, 150, and 200 mg/d) of FLV. Blood samples were collected after at least 2 weeks of treatment with the same daily dose to obtain steady-state concentrations of FLV, and 3435 C>T genotype was determined by polymerase chain reaction. FLV concentration-to-dose ratio was significantly different among 3435 C>T genotype groups at the 200 mg/d dose (P = 0.019). A post-hoc analysis revealed that FLV concentration-to-dose ratio was significantly higher in the TT genotype group as compared with the CC genotype group at the 200 mg/d dose (median value of concentration-to-dose ratio (ng/mL)/(mg/d), 0.861 vs 0.434, P = 0.026). FLV concentration-to-dose ratio was significantly higher in the CT + TT genotype group than the CC genotype group at the 200 mg/d dose (median value of concentration-to-dose ratio (ng/mL)/(mg/d), 0.618 vs 0.434, P = 0.031). At 50, 100, and 150 mg/d dose, FLV concentration-to-dose ratios were not significantly different among 3435 C>T genotype groups. At 50, 100, and 150 mg/d dose, no significant differences were found in FLV concentration-to-dose ratios between the CT + TT genotype group and CC genotype group. This study suggests that pharmacokinetics of FLV depend on ABCB1 gene polymorphism only at the 200 mg/d dose.

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.

Piloerection induced by replacing fluvoxamine with milnacipran

To present a case of piloerection after replacing fluvoxamine maleate with milnacipran hydrochloride, and to analyse this effect based on receptor occupancy theory. A 40-year-old female with a 3-year history of panic disorder was prescribed fluvoxamine 50 mg day(-1) in addition to clorazepate dipotassium and sulpiride. Depression was not improved and she complained of fatigue, lack of energy and drowsiness. These symptoms worsened within a few days of an increase in the dose of fluvoxamine to 50 mg twice daily. Since an interaction between fluvoxamine and tizanidine, prescribed by another clinic, was suspected, fluvoxamine was replaced with milnacipran 50 mg day(-1). Although her drowsiness improved, she complained of piloerection throughout her body. This symptom gradually abated within a week and when the dosage of milnacipran was increased to 100 mg day(-1) at 2 months, no further piloerection occurred. We calculated the changes in alpha(1)-adrenoceptor occupancy by endogenous norepinephrine during treatment with the usual doses of milnacipran, fluvoxamine and imipramine by using pharmacokinetic and pharmacodynamic parameters obtained from the literature. The ratios of alpha(1)-adrenoceptor occupancy by endogenous norepinephrine during the treatment with milnacipran, fluvoxamine and imipramine to that without drug were estimated to be 7.13, 1.00 and 4.12, respectively. The alpha(1)-adrenoceptor occupancy by endogenous norepinephrine was increased in a dose-dependent manner by milnacipran, whereas fluvoxamine had essentially no effect. The piloerection observed after the replacement of fluvoxamine with milnacipran in this patient appears to have been due to an increase in the alpha(1)-adrenoceptor occupancy by endogenous norepinephrine induced by milnacipran.

Rikkunshi-to attenuates adverse gastrointestinal symptoms induced by fluvoxamine

BackgroundUpper gastrointestinal (GI) symptoms such as nausea and vomiting are common adverse events associated with selective serotonin reuptake inhibitors (SSRIs), and may result in discontinuation of drug therapy in patients with depressive disorder. Rikkunshi-to (formulation TJ-43), a traditional herbal medicine, has been reported to improve upper GI symptoms and comorbid depressive symptoms in patients with functional dyspepsia. The aim of the present study was to determine if TJ-43 reduces GI symptoms and potentiates an antidepressant effect in a randomized controlled study of depressed patients treated with fluvoxamine (FLV).MethodsFifty patients with depressive disorder (19–78 years, mean age 40.2 years) were treated with FLV (n = 25) or FLV in combination with TJ-43 (FLV+TJ-43) (n = 25) for eight weeks. The following parameters of the two groups were compared: The number of patients who complained of adverse events and their symptoms; GI symptoms quality of life (QOL) score, assessed by the Gastrointestinal Symptom Rating Scale (GSRS), Japanese edition, before and two weeks after beginning treatment; and depressive symptoms assessed by the Self-Rating Depression Scale (SDS), before and 2, 4, and 8 weeks after beginning treatment.ResultsThe number of patients who complained of adverse events in the FLV+TJ-43 group (n = 6) was significantly lower than the number complaining in the FLV group (n = 13) (P < 0.05). The number of patients who complained of nausea was also lower in the FLV+TJ-43 group (n = 3) than in the FLV group (n = 9) (P < 0.05). By two weeks after treatment, GSRS scores had improved in the FLV+TJ-43 group, but not in the FLV group. SDS scores were not different between the two groups at any of the assessment points.ConclusionThis study suggests that Rikkunshi-to reduces FLV-induced adverse events, especially nausea, and improves QOL related to GI symptoms without affecting the antidepressant effect of FLV.

A Case of Depression-related Globus Pharyngeus Treated with Fluvoxamine Maleate

A Case of Depression-related Globus Pharyngeus Treated with Fluvoxamine Maleate

Somatic Symptoms in Children and Adolescents With Anxiety Disorders

To evaluate the prevalence of somatic symptoms (SSs) in children and adolescents with anxiety disorders; the relationship between SSs and anxiety severity, impairment, and child global functioning; and the impact of fluvoxamine (FLV) versus pill placebo (PBO) on reducing SSs. As part of a double-blind, placebo-controlled trial, 128 children (mean age, 10.8 years; range, 6-17) with DSM-IV anxiety disorders (i.e., social, separation, and generalized anxiety) were assessed by expert clinicians on 16 SSs using the Pediatric Anxiety Rating Scale. The most common SSs at baseline were restlessness (74%), stomachaches (70%), blushing (51%), palpitations (48%), muscle tension (45%), sweating (45%), and trembling/shaking (43%). Older children (age 12 and older) reported more SSs than younger children, boys and girls reported similar numbers of SSs, and SSs were higher among children with than without generalized anxiety disorder. SSs were significantly and positively correlated with anxiety severity, impairment, and global functioning. Pre-/postreductions in SSs were statistically significant in both PBO and FLV conditions; however, FLV was superior to PBO in reducing SSs. SSs are highly prevalent among children and adolescents with anxiety disorders and are associated with greater anxiety severity and impairment. Treatment with FLV was effective in reducing rather than increasing SSs. The high rates of SSs in youths with each of the three anxiety disorders suggest a re-evaluation of SSs in the DSM-IV diagnostic criteria for the most common anxiety disorders among children and adolescents.

The effects of human CYP2C8 genotype and fluvoxamine on the pharmacokinetics of rosiglitazone in healthy subjects

To determine the effect of CYP2C8 genotype and of fluvoxamine on the pharmacokinetics of rosiglitazone. Twenty-three healthy subjects with the following genotypes were included in a two-phase, open-label, cross-over trial: CYP2C8*3/ *3 (n = 3), CYP2C8*1/ *3 (n = 10) and CYP2C8*1/ *1 (n = 10). In Phase A, the subjects were given 4 mg rosiglitazone as a single oral dose. In Phase B, the subjects were treated with multiple oral doses of 50 mg fluvoxamine maleate for 3 days prior to the single oral administration of 4 mg rosiglitazone. Plasma concentrations of rosiglitazone and relative amounts of N-desmethylrosiglitazone were measured in both phases for 24 h after drug administration. The pharmacokinetics of rosiglitazone and N-desmethylrosiglitazone were not significantly different between the CYP2C8 genotypic groups. Fluvoxamine caused a statistically significant (P = 0.0066) increase in the AUC(0-infinity) of rosiglitazone, with a geometric mean ratio of 1.21 [95% confidence interval (CI) 1.06-1.39]. The elimination half-life (t(1/2)) was also significantly higher (P = 0.0203) with a geometric mean ratio of 1.38 [95% CI 1.06-1.79]. The coadministration of fluvoxamine had no influence on the pharmacokinetics of N-desmethylrosiglitazone. The importance of the CYP2C8*3 mutation in the in vivo metabolism of rosiglitazone could not be confirmed. Fluvoxamine increased the AUC(0-infinity) and t(1/2) of rosiglitazone moderately and hence may be a weak inhibitor of CYP2C8.

A case of fluvoxamine discontinuation-related hypomania

A case of fluvoxamine discontinuation-related hypomania

Effects of Caffeine on the Kinetics of Fluvoxamine and its Major Metabolite in Plasma After a Single Oral Dose of the Drug

The effects of caffeine on the kinetics of fluvoxamine (FLV) and its major metabolite fluvoxamino acid (FLA) in plasma, after a single oral dose of the drug, were studied in 12 healthy male volunteers. The subjects received caffeine 300 mg/d or placebo for 11 days in a double-blind randomized crossover manner, and on the eighth day they received a single oral 50-mg dose of FLV. Blood sampling and pharmacodynamic evaluation were conducted up to 72 hours after FLV dosing. Plasma concentrations of FLV and FLA were measured by high-performance liquid chromatography. Caffeine significantly decreased the plasma concentrations at 6 time points (P<0.05) and total area under the plasma concentration-time curve (156.5+/-51.7 vs. 118.9+/-38.2 ng/h/mL, P<0.01) of FLV. Plasma concentration and pharmacokinetic parameters of FLA were not affected by caffeine. Caffeine induced no significant change in the pharmacodynamic effects of FLV. The present study suggests that caffeine slightly induces the metabolism of FLV, probably mediated by CYP1A2.

Do Antidepressants Increase Suicide Risk? Maybe Not

In 2004, the FDA issued an advisory stating that bupropion, citalopram, escitalopram, paroxetine, fluoxetine, fluvoxamine, mirtazapine, nefazodone,