Characterization of microminipig as a laboratory animal for safety pharmacology study by analyzing fluvoxamine-induced cardiovascular and dermatological adverse reactions.

Fluvoxamine is a selective serotonin-reuptake inhibitor, of which IC50 values for serotonin- and noradrenaline-uptake process were reported to be 3.8 and 620 nmol/L, respectively, also known to directly inhibit cardiac Na+, Ca2+, and K+ channels. We characterized microminipig as a laboratory animal by analyzing fluvoxamine-induced cardiovascular and dermatological responses under halothane anesthesia. Fluvoxamine maleate was infused in doses of 0.1, 1, and 10 mg/kg over 10 min with a pause of 20 min (n = 4). The peak plasma concentrations were 35, 320, and 1906 ng/mL, of which free plasma concentrations were estimated as 20, 187, and 1108 nmol/L, respectively. The low and middle doses did not alter any cardiovascular variable. The high dose increased heart rate and mean blood pressure, prolonged QRS width, but shortened QT interval, whereas no significant change was detected in PR interval or QTcF. Moreover, it induced systemic erythema on the skin. Pretreatment of H1/5-HT2A antagonist cyproheptadine hydrochloride sesquihydrate in a dose of 0.3 mg/kg significantly attenuated the fluvoxamine-induced pressor response; but tended to further enhance sinus automaticity, atrioventricular nodal conduction; and ventricular repolarization in addition to intraventricular conduction delay; whereas it markedly suppressed onset of systemic erythema (n = 4). In microminipigs, cardiovascular adverse effects of the high dose may be manifested as a sum of its inhibitory action on the cardiac ionic channels and its stimulatory effects on serotonergic and adrenergic systems, whereas dermatologic reaction can be induced primarily through H1/5-HT2A receptor-dependent mechanism. Thus, microminipigs may be used for analyzing such multifarious adverse events of clinical serotonergic pharmacotherapy.

[Effects of neonatal fluvoxamine administration to white rats and their correction by semax treatment].

The aim of this work was to study the delayed effects of chronic neonatal administration of the selective serotonin reuptake inhibitor fluvoxamine (FA) to white rat pups and to estimate the possibility to correct these effects by treatment with semax. Fluvoxamine was injected intraperitoneally at a dose of 10 mg/kg from postnatal days 1 to 14, and semax was injected intranasally at a dose of 0.05 mg/kg from postnatal days 15 to 28. It was shown that neonatal FA administration produced a significant delay in animal somatic growth. A loss in body weight was detected both during FA administration and 4-6 weeks after the last injection. Furthermore, FA administration increased the anxiety level and disturbed the learning ability of animals. The negative consequences of neonatal FA administration were largely compensated by Semax.

Effect of combination of aripiprazole with carbamazepine and fluvoxamine on liver functions in experimental animals.

OBJECTIVES: Aripiprazole, a new atypical antipsychotic drug extensively metabolized by enzyme CYP3A4, is found to produce asymptomatic elevation of serum transaminase levels on long-term treatment. The present study aims to evaluate the hepatotoxic effect of aripiprazole when coprescribed with carbamazepine and fluvoxamine. MATERIALS AND METHODS: The rats were subjected to chronic treatment with two different doses, therapeutic dose (TD) and maximum therapeutic dose (MTD), of aripiprazole in combination with carbamazepine and fluvoxamine. The changes in hepatic function was assessed by various biochemical liver enzyme markers like serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALP), total bilirubin, histological studies, and physical parameters (liver weight, liver volume, and body weight). RESULTS: The combination of aripiprazole with fluvoxamine at both TD and MTD showed the hepatic damage and significant elevation in serum transaminase level which is supported by histological reports. The coadministration of aripiprazole with carbamazepine leads to significant decrease in blood concentration of aripiprazole possibly due to induction of enzyme CYP3A4 resulting in loss or reduction of clinical efficacy. CONCLUSIONS: There would be an accumulation of aripiprazole when coadministered with fluvoxamine, a known inhibitor of CYP3A4, leading to hepatic damage and reduction in aripiprazole when administered along with carbamazepine. Therefore, aripiprazole with fluvoxamine and carbamazepine should be coprescribed with caution. The patients should be monitored for signs of adverse effects like hepatic damage or decreased efficacy of these drugs.

An NMR investigation of the structure, function and role of the hERG channel selectivity filter in the long QT syndrome.

The human ether-a-go-go-related gene (hERG) voltage-gated K(+) channels are located in heart cell membranes and hold a unique selectivity filter (SF) amino acid sequence (SVGFG) as compared to other K(+) channels (TVGYG). The hERG provokes the acquired long QT syndrome (ALQTS) when blocked, as a side effect of drugs, leading to arrhythmia or heart failure. Its pore domain - including the SF - is believed to be a cardiotoxic drug target. In this study combining solution and solid-state NMR experiments we examine the structure and function of hERG's L(622)-K(638) segment which comprises the SF, as well as its role in the ALQTS using reported active drugs. We first show that the SF segment is unstructured in solution with and without K(+) ions in its surroundings, consistent with the expected flexibility required for the change between the different channel conductive states predicted by computational studies. We also show that the SF segment has the potential to perturb the membrane, but that the presence of K(+) ions cancels this interaction. The SF moiety appears to be a possible target for promethazine in the ALQTS mechanism, but not as much for bepridil, cetirizine, diphenhydramine and fluvoxamine. The membrane affinity of the SF is also affected by the presence of drugs which also perturb model DMPC-based membranes. These results thus suggest that the membrane could play a role in the ALQTS by promoting the access to transmembrane or intracellular targets on the hERG channel, or perturbing the lipid-protein synergy.

Neonatal exposure to fluoxetine and fluvoxamine alteres spine density in mouse hippocampal CA1 pyramidal neurons.

Some women in childbearing ages take selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and fluvoxamine for treating psychiatric symptoms. However, these compounds may cause some side effects to their children. It has been identified that early life exposure to SSRIs increased the chance of developing mood disorders and the biological basis is still unclear. Here, we studied the effects of neonatal exposure to SSRIs on neuronal morphology. We used GFP-transgenic mice to investigate the acute and long-lasting effects of early life exposure to SSRIs on dendritic spine density of CA1 neurons. We found that 18-day drug applications of fluoxetine and fluvoxamine significantly reduced spine density of basal dendrites at postnatal day 22 (P22), but only fluvoxamine caused a reduction of spine density of apical dendrites. Interestingly, compared with the control group, the spine densities of basal dendrites after fluoxetine and fluvoxamine exposure and the spine density of apical dendrites after fluoxetine exposure increased in adult mice at the age of P90. We also observed impaired locomotor activity in adult mice after exposure to SSRIs. Our findings demonstrated that neonatal exposure to SSRIs was capable of influencing the morphological plasticity of excitatory synapses. It raised the caution for clinical use of SSRIs.

Toxicity and hazard of selective serotonin reuptake inhibitor antidepressants fluoxetine, fluvoxamine, and sertraline to algae.

The toxicity of SSRIs to algae/phytoplankton was investigated using the US EPA ECOSAR, acute single-species growth inhibition assays, species sensitivity distributions (SSDs), and an outdoor microcosm mixture experiment. Worst-case ECOSAR estimates of SSRI toxicity to algae ranged from 0.73 to 13.08 mg/L. Sertraline was the most toxic SSRI tested in single-species growth inhibition assays followed by fluoxetine and fluvoxamine with worst-case 96-h IC10s of 4.6, 31.3, and 1662 microg/L, respectively. HC5s of 2.4, 3.6, and 1100 microg/L were estimated, respectively, for sertraline, fluoxetine, and fluvoxamine toxicity to algae-using SSDs. Microcosm phytoplankton structural endpoints were more sensitive than functional endpoints in the short term. However, in the long term, structural endpoints were resilient and functional endpoints remained impacted even after a period of recovery. The worst-case EC10 determined from the outdoor microcosm mixture toxicity to phytoplankton communities was 15.2 nM. Although SSRIs are toxic to algae, hazard quotients using worst-case PECs represent a margin of safety of 20 to phytoplankton. Although SSRIs do not appear to pose a hazard to primary production, this assessment is not protective of higher aquatic organisms and further research into the chronic toxicity to low levels of SSRIs to higher-level aquatic species is recommended.

Effects of co-administration of a selective serotonin reuptake inhibitor and monoamine oxidase inhibitors on 5-HT-related behavior in rats.

5-hydroxytryptamine (5-HT) syndrome is a dangerous condition of 5-HT excess that can occur in the case of co-administration of a monoamine oxidase (MAO) inhibitor and a serotonin reuptake inhibitor (SSRI). The goal of the present study was to investigate the effects of acute administration of MAO inhibitors and subchronic administration of fluvoxamine on 5-HT-related behaviors (head shaking and 5-HT syndrome) in rats treated with 5-hydroxytryptophan (5-HTP). Administration of the non-selective MAO inhibitor, pargyline, and the selective MAO-A inhibitor, clorgyline, resulted in 5-HT syndrome in 5-HTP-treated rats, and subchronic co-administration of fluvoxamine intensified the syndrome. However, administration of the selective MAO-B inhibitor, selegiline, did not induce 5-HT syndrome with or without subchronic fluvoxamine co-administration. These data suggest that non-selective MAO and selective MAO-A inhibitors can induce 5-HT syndrome in humans when co-administered with SSRI. Further, the risk of 5-HT syndrome may be lower with the selective MAO-B inhibitor, selegiline.

Acute and chronic toxicity of five selective serotonin reuptake inhibitors in Ceriodaphnia dubia.

Contamination of surface waters by pharmaceutical chemicals has raised concern among environmental scientists because of the potential for negative effects on aquatic organisms. Of particular importance are pharmaceutical compounds that affect the nervous or endocrine systems because effects on aquatic organisms are possible at low environmental concentrations. Selective serotonin reuptake inhibitors (SSRIs) are drugs used to treat clinical depression in humans, and have been detected in low concentrations in surface waters. In this investigation, the acute and chronic toxicity of five SSRIs (fluoxetine, Prozac; fluvoxamine, Luvox; paroxetine, Paxil; citalopram, Celexa; and sertraline, Zoloft) were evaluated in the daphnid Ceriodaphnia dubia. For each SSRI, the 48-h median lethal concentration (LC50) was determined in three static tests with neonate C. dubia, and chronic (8-d) tests were conducted to determine no-observable-effect concentrations (NOEC) and lowest-observable-effect concentrations (LOEC) for reproduction endpoints. The 48-h LC50 for the SSRIs ranged from 0.12 to 3.90 mg/L and the order of toxicity of the compounds was (lowest to highest): Citalopram, fluvoxamine, paroxetine, fluoxetine, sertraline. Mortality data for the 8-d chronic tests were similar to the 48-h acute data. The SSRIs negatively affected C. dubia reproduction by reducing the number of neonates per female, and for some SSRIs, by reducing the number of broods per female. For sertraline, the most toxic SSRI, the LOEC for the number of neonates per female was 0.045 mg/L and the NOEC was 0.009 mg/L. Results indicate that SSRIs can impact survival and reproduction of C. dubia; however, only at concentrations that are considerably higher than those expected in the environment.

Effects of fluvoxamine, a selective serotonin re-uptake inhibitor, on serotonin release from the mouse isolated ileum.

The presence of nausea and vomiting is problematic for all selective serotonin re-uptake inhibitors (SSRIs), and their usefulness as anti-depressants is limited in this respect. In an attempt to examine the background of SSRI-induced emesis, the present study aims to describe the role of 5-hydroxytryptamine (serotonin:5-HT) from the viewpoint of 5-HT release in the mouse-isolated ileum. In this study, it was demonstrated that 5-HT release from the mouse-isolated ileum was significantly increased by fluvoxamine at a concentration of 10(-6) M. Also, it was demonstrated that granisetron, a 5-HT3 receptor antagonist, inhibited significantly the increase in fluvoxamine (10(-6) M) -induced 5-HT release. The effect of granisetron on fluvoxamine-induced 5-HT release was occurred in a concentration-dependent manner. The present study demonstrated for the first time that the SSRI-induced increase in 5-HT release from the isolated ileum was significantly inhibited by 5-HT3 receptor antagonist. These results suggest that 5-HT3 receptors might be involved in SSRI-induced 5-HT release from the mouse isolated ileal tissue. Fluvoxamine (10(-6) M)-induced 5-HT release was inhibited concentration -dependently by the concomitant perfusion of diltiazem. The results suggest that L-type calcium channel might be also involved in SSRI-induced 5-HT release from the isolated ileum. Furthermore, tetrodotoxin (10(-6) M) completely inhibited the increase in 5-HT release induced by fluvoxamine. This finding suggests that the increase of 5-HT induced by fluvoxamine involves enterochromaffin (EC) cell stimulation via an inter-neuron pathway in the gastrointestinal tract (GI). SSRI initiates an increase in the concentration of 5-HT in the GI tract. 5-HT released from the EC cells of the intestinal mucosa may stimulate the 5-HT3 receptors on vagal afferent nerve fibers. This depolarization of vagal afferents may result in a 5-HT increase in the brainstem and, thus, lead to emesis.

A comparative pharmacodynamic study of the arrhythmogenicity of antidepressants, fluvoxamine and imipramine, in guinea pigs.

Among several classes of antidepressants, tricyclic antidepressants are known to prolong QTc intervals (QT interval corrected by heart rate) in electrocardiograms, while selective serotonin uptake inhibitors (SSRI) are considered to be devoid of arrhythmogenicity. In this study, we aimed to compare the arrhythmogenic potencies of imipramine (IMI), a typical tricyclic antidepressant, and fluvoxamine (FLV), an SSRI, at therapeutic and supratherapeutic concentrations using guinea pigs in vivo. Guinea pigs were anesthetized, and IMI (10 and 20 mg/kg/h) or FLV (20 mg/kg/h) was intravenously administered for 90 minutes to obtain the time-courses of drug concentrations in plasma and the changes in the QTc intervals during and after the drug administration. IMI induced distinct QTc prolongation in a dose-dependent manner, while FLV prolonged QTc intervals only slightly. A pharmacokinetic-pharmacodynamic analysis revealed that the potency for QTc prolongation of IMI was 1.7-fold higher than that of FLV. Taking the therapeutic concentration into account, the clinical risk of FLV for QTc prolongation was suggested to be 5-fold lower than that of IMI. Therefore, this SSRI agent was suggested to be safer than the tricyclic antidepressant for patients with cardiac risk factors, including arrhythmia, or for those taking other arrhythmogenic drugs concomitantly.

Selective serotonin reuptake inhibitors fluoxetine and fluvoxamine induce hyperglycemia by different mechanisms.

The effects of the selective serotonin reuptake inhibitors, fluoxetine and fluvoxamine, on plasma glucose levels were investigated in mice. Both fluoxetine and fluvoxamine elicited significant hyperglycemia, while a selective noradrenaline reuptake inhibitor maprotiline had no effect. Fluoxetine and fluvoxamine did not change serum insulin levels, although they elicited hyperglycemia. Pretreatment with the serotonin (5-hydroxytryptamine, 5-HT) depleter, p-chlorophenylalanine (pCPA), abolished fluvoxamine-induced hyperglycemia, although pCPA did not affect the fluoxetine-induced glycemic effects. These results suggest that the selective serotonin reuptake inhibitors fluoxetine and fluvoxamine induce hyperglycemia by inhibition of insulin release. Moreover, our findings indicate that the glycemic effects of these drugs are differentially associated with serotonergic mechanisms.