Exploring the Inhibitory Mechanism of Approved Selective Norepinephrine Reuptake Inhibitors and Reboxetine Enantiomers by Molecular Dynamics Study.

Selective norepinephrine reuptake inhibitors (sNRIs) provide an effective class of approved antipsychotics, whose inhibitory mechanism could facilitate the discovery of privileged scaffolds with enhanced drug efficacy. However, the crystal structure of human norepinephrine transporter (hNET) has not been determined yet and the inhibitory mechanism of sNRIs remains elusive. In this work, multiple computational methods were integrated to explore the inhibitory mechanism of approved sNRIs (atomoxetine, maprotiline, reboxetine and viloxazine), and 3 lines of evidences were provided to verify the calculation results. Consequently, a binding mode defined by interactions between three chemical moieties in sNRIs and eleven residues in hNET was identified as shared by approved sNRIs. In the meantime, binding modes of reboxetine's enantiomers with hNET were compared. 6 key residues favoring the binding of (S, S)-reboxetine over that of (R, R)-reboxetine were discovered. This is the first study reporting that those 11 residues are the common determinants for the binding of approved sNRIs. The identified binding mode shed light on the inhibitory mechanism of approved sNRIs, which could help identify novel scaffolds with improved drug efficacy.

Pharmacokinetics of the antidepressant drug viloxazine in normal subjects and in epileptic patients receiving chronic anticonvulsant treatment.

In order to evaluate the influence of chronic antiepileptic drug treatment on the kinetics of the antidepressant viloxazine (VLX), six drug-free control subjects and six epileptic patients treated with one or two anticonvulsants (phenobarbital, carbamazepine or phenytoin) were given a single oral dose of VLX (200 mg). On a separate occasion, the patients were also given 200 mg VLX by IV infusion. Plasma VLX levels were determined by GLC. Following oral dosing, VLX was rapidly absorbed from the gastrointestinal tract (peak levels at 0.5-4 h); plasma level profiles showed a considerable interindividual variability but did not differ significantly between patients and controls. Terminal half-lives were 4.3 +/- 1.5 h in the patients and 4.3 +/- 1.8 h in the controls. Clearance and volume of distribution calculated after IV dosing in the patients were 124 +/- 11 ml h-1 kg-1 and 0.73 +/- 0.28 l/kg, respectively. The absolute oral availability was 85 +/- 14%. At variance with findings reported for other antidepressants, VLX kinetics do not appear to be significantly altered by concurrent treatment with enzyme-inducing antiepileptic drugs.

Age-related differences in kinetics and side-effects of viloxazine in man and their clinical implications.

Dose kinetics and side effects of viloxazine (VLX) in 16 healthy volunteers (range age 25-90 years) were studied after single oral administration of 200 mg of VLX. Significant differences in peak plasma values (P less than 0.01), t1/2 (P less than 0.01) and Cl/F (P less than 0.05) were found between subjects under 50 and over 60 years. Positive correlations were found between age and peak plasma values (P less than 0.05), age and AUC (P less than 0.01). No correlations were found between age, t1/2 and Cl/F, due to the high interindividual variability in pharmacokinetic profiles. Total reported and observed side effects scores were higher overall in subjects under 50 years than over 60 years and were inversely correlated to AUC (P less than 0.05). Drowsiness was inversely related to the age of subjects (P less than 0.05). Our data support the importance of single dose kinetic studies, particularly for new antidepressants, in relation to age, both to emphasize differences in pharmacokinetic profiles and to predict side effects during chronic treatment.

Pharmacokinetics of viloxazine hydrochloride in man.

The pharmacokinetic characteristics of a new antidepressant, viloxazine hydrochloride, were investigated in five males and five females to study sex differences. Plasma levels were determined over a period of 9 h after a single dose of viloxazine of 100 mg (expressed as base). The half life of the drug was in the range of 2.19 - 4.21 for females and 2.61 - 4.31 h for males. The maximum plasma levels occurred in 29 - 171 min of the oral dose for females and 54 - 155 min for males. They reached 1382 - 1769 ng/ml-l for females and 1108 - 2932 ng/ml for males. Pharmacokinetic data were not statistically different between males and females.

Viloxazine: a review of the literature.

In animal pharmacological studies viloxazine has shown similarities to imipramine. The antidepressant effects of the substance were independently recognized in seven uncontrolled clinical trials and verified in 11 published standard controlled clinical studies in which viloxazine in the dosage range from 150- to 300-mg dosage was equal in overall therapeutic efficacy to imipramine and amitriptyline, but produced a lower incidence of side effects.

Effects of viloxazine, its optical isomers and its major metabolites on biogenic amine uptake mechanisms in vitro and in vivo.

Viloxazine hydrochloride (ICI 58,834, VIVALAN) a chemically novel antidepressant, shows selective inhibition of noradrenaline uptake into mouse heart in vivo and into rat brain in vitro. The noradrenaline uptake inhibitory activity resides primarily in one of the two optically active isomers, and it is suggested that in the conformation adopted for uptake by noradrenaline, the aryl and the amino groups are trans. In a comparison of in vivo and in vitro potency, tri- and tetracyclic antidepressants exhibit a good correlation. However, viloxazine possesses higher in vivo activity than would be expected from in vitro studies. The latter finding cannot be readily explained on the basis of known pharmacokinetic or metabolic factors.

[Synopsis of psychopathological, electroencephalographical, and pharmacokinetic variables during antidepressive treatment with viloxazine (author's transl)]. / Synopsis psychopathologischer, elektroenzephalographischer und pharmakokinetischer Parameter unter einer antidepressiven Therapie mit Viloxazin.

In order to achieve a more differentiated assessment of the profile and time course of treatment with a new antidepressant drug, several psychiatric, neurophysiological, and biochemical parameters were examined in a double-blind study (viloxazine versus amitriptyline). Special attention was directed to the use of a time-blind audiovisual technique. The TV technique allowed to demonstrate an earlier onset of the therapeutic effect under viloxazine, which is in good agreement with the cross-sectional and longitudinal profile of viloxazine as regards pharmacokinetics and EEG.

Blood level studies with viloxazine hydrochloride in man.

1 The pharmacokinetic characteristics of a new antidepressant, viloxazine hydrochloride, (ICI 58,834, Vivalan), have been investigated in four separate studies. 2 In Study 1, blood levels were measured over a period of 24 h after single doses of viloxazine hydrochloride from 10-100 mg (expressed as base). In Study 2, blood levels were measured over 24 h, during which three single doses of viloxazine hydrochloride (80 mg, expressed as base) were given 4 h apart. In Study 3, blood samples and urine and faeces were collected for 96 h after doses of 40 and 100 mg of [14C] viloxazine hydrochloride (40 muCi). In Study 4, 1 h blood levels were measured at weekly intervals during a comparative clinical trial in which viloxazine was given at a dose of 100 mg four times a day. 3 The half-life of the drug is in the range 2-5 h with maximum blood levels occurring in 1-4 h of the oral dose. Maximum blood levels are proportional to the oral dose given over the range studied (0.76(mug/ml)/(mg/kg)). The drug is very well absorbed orally, only 2% being found in faeces. Repeated dosing at 4 hourly intervals leads to slightly higher blood levels after the second, but not subsequent, doses. No accumulation was seen from week to week in depressed patients. No regular sex difference was seen in the pharmacokinetic characteristics of viloxazine hydrochloride but two females in one study did show a markedly higher maximum blood level and apparently longer half-life than the males. 4 It is concluded that viloxazine is rapidly and almost totally absorbed after an oral dose, and has a shorter half-life than the tricyclic antidepressants; therapy with it should be easily controllable.