Reboxetine is metabolized by dealkylation, hydroxylation and oxidation followed by glucuronide or sulphate conjugation. It is metabolized by the cytochrome P450 CYP isoenzyme 3A4.
瑞波西汀通过脱烷基化、羟基化和氧化作用进行代谢，随后与葡萄糖醛酸或硫酸结合。它由细胞色素P450 CYP同工酶3A4代谢。
Reboxetine is metabolized by dealkylation, hydroxylation and oxidation followed by glucuronide or sulphate conjugation. It is metabolized by the cytochrome P450 CYP isoenzyme 3A4.
The purpose of this study was to compare the disposition and the metabolic pattern of Reboxetine in several species, including man. (14)C-Reboxetine was given orally to the rat, the dog, the monkey (5 mg/kg) and man (2 and 4 mg/kg). Radioactivity was eliminated both by the renal and faecal route in the rat and the dog, mainly in urine in the monkey and man. Reboxetine was extensively metabolized. A number of urinary metabolites were quantified by radio-HPLC and tentatively identified by comparison with the retention times of reference compounds. Suggested routes of metabolic transformation are: 2-O-dealkylation; hydroxylation of the ethoxyphenoxy ring; oxidation of the morpholine ring; morpholine ring-opening; and combinations of these. Metabolites were partially or completely conjugated with glucuronic acid and/or sulphuric acid.
Reboxetine is predominantly metabolized in vitro via cytochrome P4503A (CYP3A4). In vitro studies have shown that reboxetine does not inhibit the activity of the following isozymes of cytochrome P450: CYP1A2, CYP2C9, CYP2C19, and CYP2E1. Reboxetine inhibits both CYP2D6 and CYP3A4 with low binding affinities, but has shown no effect on the in vivo clearance of drugs metabolized by these enzymes. Reboxetine should be co-prescribed with caution with potent inhibitors of CYP3A4.
◉ Summary of Use during Lactation:Reboxetine is not approved for marketing in the United States by the U.S. Food and Drug Administration, but is available in other countries. Limited information indicates that maternal doses of up to 10 mg daily produce low levels in milk and appear to not result in any adverse effects in breastfed infants. Until more data are available, reboxetine should be used with careful monitoring during breastfeeding.
◉ Effects in Breastfed Infants:Four infants whose mothers had postpartum depression had been breastfed (extent not stated) for 1.3 to 2.1 months during maternal reboxetine therapy at an average dose of 6.5 mg (79 mcg/kg) daily. One of the mothers was also taking escitalopram 20 mg daily and another was taking sertraline 300 mg daily. None of the infants exhibited any adverse reactions. Three of the infants had normal Denver developmental scores; the fourth whose mother was taking reboxetine had a developmental age of only 71% of normal, but the problem predated maternal reboxetine therapy.
Five women used reboxetine during pregnancy and lactation (extent not stated) in unspecified doses. No adverse effects were noted in their infants and normal developmental milestones were reported.
◉ Effects on Lactation and Breastmilk:Reboxetine increased serum prolactin in male subjects. The relevance of this finding to nursing mothers is not clear. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.
An observational study looked at outcomes of 2859 women who took an antidepressant during the 2 years prior to pregnancy. Compared to women who did not take an antidepressant during pregnancy, mothers who took an antidepressant during all 3 trimesters of pregnancy were 37% less likely to be breastfeeding upon hospital discharge. Mothers who took an antidepressant only during the third trimester were 75% less likely to be breastfeeding at discharge. Those who took an antidepressant only during the first and second trimesters did not have a reduced likelihood of breastfeeding at discharge. The antidepressants used by the mothers were not specified.
A retrospective cohort study of hospital electronic medical records from 2001 to 2008 compared women who had been dispensed an antidepressant during late gestation (n = 575) to those who had a psychiatric illness but did not receive an antidepressant (n = 1552) and mothers who did not have a psychiatric diagnosis (n = 30,535). Women who received an antidepressant were 37% less likely to be breastfeeding at discharge than women without a psychiatric diagnosis, but no less likely to be breastfeeding than untreated mothers with a psychiatric diagnosis. None of the mothers were taking reboxetine.
In a study of 80,882 Norwegian mother-infant pairs from 1999 to 2008, new postpartum antidepressant use was reported by 392 women and 201 reported that they continued antidepressants from pregnancy. Compared with the unexposed comparison group, late pregnancy antidepressant use was associated with a 7% reduced likelihood of breastfeeding initiation, but with no effect on breastfeeding duration or exclusivity. Compared with the unexposed comparison group, new or restarted antidepressant use was associated with a 63% reduced likelihood of predominant, and a 51% reduced likelihood of any breastfeeding at 6 months, as well as a 2.6-fold increased risk of abrupt breastfeeding discontinuation. Specific antidepressants were not mentioned.
In vitro metabolism studies indicate that reboxetine is primarily metabolised by the CYP3A4 isozyme of cytochrome P450; reboxetine is not metabolized by CYP2D6. Therefore potent inhibitors of CYP3A4 (ketoconazole, nefazodone, erythromycin and fluvoxamine), would be expected to increase plasma concentrations of reboxetine. In a study in healthy volunteers, ketoconazole, a potent inhibitor of CYP3A4, was found to increase plasma concentrations of the reboxetine enantiomers by approximately 50%. Because of reboxetine's narrow therapeutic margin, inhibition of elimination is a major concern. Reboxetine, therefore should not be given together with drugs known to inhibit CYP3A4 such as azole antifungal agents, macrolide antibiotics such as erythromycin, or fluvoxamine.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
相互作用
MAO抑制剂与瑞波西汀联合使用应避免，因为根据它们的的作用机制，存在潜在风险（类似酪胺效应）。
Concomitant use of MAO-inhibitors and reboxetine should be avoided in view of the potential risk (tyramine-like effect) based on their mechanisms of action.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
相互作用
尽管没有来自临床研究的数据，但考虑到同时使用排钾利尿剂，应考虑低钾血症的可能性。
Although data are not available from clinical studies, the possibility of hypokalaemia with concomitant use of potassium losing diuretics should be considered.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
相互作用
联用麦角衍生物和瑞波西汀可能会导致血压升高。
Concomitant use of ergot derivatives and reboxetine might result in increased blood pressure.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
吸收
瑞波西汀口服给药后能迅速且广泛地被吸收。
Reboxetine is rapidly and extensively absorbed following oral administration.
Multiple samples of blood and milk were obtained over a dose interval at steady-state from four women who were taking reboxetine for postnatal depression. Drug concentrations in plasma and milk were measured by high performance liquid chromatography and milk/plasma ratio (M/P), absolute infant dose and relative infant dose were estimated by standard methods. Their four, breastfed, infants were also examined clinically, and a blood sample was taken for drug analysis. The median (range) dose taken by the women was 6 (4-10) mg/day. There was no significant difference in reboxetine concentration between paired fore-and hind-milk samples. The mean (95% CI) M/P was 0.06 (0.03, 0.09). Absolute infant dose was 1.7 (0.7, 2.4) ug/kg/day for reboxetine while the relative infant dose was 2.0% (1.3, 2.7%). ... The concentrations of reboxetine in plasma from the four infants were <4 ug/L, 2.6 ug/L, 2.3 ug/L and 5 ug/L, respectively.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
瑞波西汀已知会分泌至母乳中。
Reboxetine is known to be excreted in breast milk.
The drug appears to be distributed into total body water. Reboxetine is 97% bound to human plasma proteins in young and 92% in elderly (with affinity markedly higher for alpha1 acid glycoprotein than albumin), with no significant dependence of the concentration of drug.
After oral administration of a single 4 mg reboxetine dose to healthy volunteers, peak levels of about 130 ng/mL are achieved within 2 hr post-dosing. Data indicate that absolute bioavailability is at least 60%. Reboxetine plasma levels decreased monoexponentially with a half-life of about 13 hr. Steady-state conditions are observed within 5 days. Linearity of the pharmacokinetics was shown in the range of single oral doses in the clinically recommended dose-ranges.
[EN] COMPOUNDS AND THEIR USE AS BACE INHIBITORS<br/>[FR] COMPOSÉS ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE BACE
申请人：ASTRAZENECA AB
公开号：WO2016055858A1
公开（公告）日：2016-04-14
The present application relates to compounds of formula (I), (la), or (lb) and their pharmaceutical compositions/preparations. This application further relates to methods of treating or preventing Αβ-related pathologies such as Down's syndrome, β- amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia, including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease.
The present invention provides certain imidazole carboxamide derivatives, pharmaceutical compositions thereof, methods of using the same and processes for preparing the same.
本发明提供了某些咪唑羧酰胺衍生物，其药物组合物，使用方法以及制备方法。
[EN] DIAZABICYCLO[4.3.1]DECANE DERIVATIVES FOR TREATMENT OF PSYCHIATRIC DISORDERS<br/>[FR] DÉRIVÉS DE DIAZABICYCLO[4.3.1]DÉCANE POUR LE TRAITEMENT DE TROUBLES PSYCHIATRIQUES
申请人：MAX PLANCK GES ZUR FÖRDERUNG DER WISSENSCHAFTEN E V
公开号：WO2015110271A1
公开（公告）日：2015-07-30
The present invention relates to diazabicyclo[4.3.1 ]decane derivatives (I), pharmaceutically acceptable salts of these compounds and pharmaceutical compositions containing at least one of these compounds together with pharmaceutically acceptable carrier, excipient and/or diluents. Said diazabicyclo[4.3.1]decane derivatives are specific inhibitors of the FK506 binding proteins (FKBP's) and can be used for prophylaxis and/or treatment of psychiatric disorders and neurodegenerative diseases, disorders and conditions.
Diazabicyclo[4.3.1]decane derivatives for treatment of psychiatric disorders
申请人：Max-Planck-Gesellschaft zur Förderung
der Wissenschaften e.V.
公开号：EP2899192A1
公开（公告）日：2015-07-29
The present invention relates to diazabicyclo[4.3.1]decane derivatives of formula (I), pharmaceutically acceptable salts of these compounds and pharmaceutical compositions containing at least one of these compounds together with pharmaceutically acceptable carrier, excipient and/or diluents. Said diazabicyclo[4.3.1]decane derivatives are inhibitors of the FK506 binding protein (FKBP's) and can be used for prophylaxis and/or treatment of psychiatric disorders and neurodegenerative diseases, disorders and conditions.
DIAZABICYCLO[4.3.1]DECANE DERIVATIVES FOR TREATMENT OF PSYCHIATRIC DISORDERS
申请人：MAX-PLANCK-GESELLSCHAFT ZUR FÖRDERUNG DER WISSENSCHAFTEN E.V.
公开号：US20170002003A1
公开（公告）日：2017-01-05
The present invention relates to diazabicyclo[4.3.1]decane derivatives, pharmaceutically acceptable salts of these compounds and pharmaceutical compositions containing at least one of these compounds together with pharmaceutically acceptable carrier, excipient and/or diluents. Said diazabicyclo[4.3.1]decane derivatives can be used for prophylaxis and/or treatment of psychiatric disorders and neurodegenerative diseases, disorders and conditions.
