Dothiepin-X-oxide is the major metabolite. Northiaden (desmethyl-dothiepin) is an N-demethylated derivative. Both metabolites have antidepressant activity.
Twenty-seven healthy men received three single oral doses of 50-, 100-, and 150-mg dothiepin hydrochloride capsules in a three-way randomized, crossover dose-proportionality study. ... Plasma concentration-time profiles of the three major metabolites of dothiepin, the S-oxide derivative of dothiepin, N,N-dimethyl[b,e]thiepin-delta 11(6 H), gamma-propylamine 5-oxide (2), the demethyl derivative, N-methyldibenzo[b,e]thiepin-delta 11(6 H), gamma-propylamine (3) and the demethyl S-oxide derivative N-methyldibenzo[b,e]thiepin-delta 11(6 H), gamma-propylamine 5-oxide (4), were described by a one-compartment model with apparent first-order formation. The AUC infinity values of the S-oxide 2 and the demethyl S-oxide 4 increased proportionally with dose. The dose proportionality of the demethyl metabolite 3 may not be ascertained from the data in this study. The corresponding half-lives of the three metabolites, which are dose independent, were approximately 24, 28, and 40 hr, respectively. /Dothiepin Hydrochloride/
Only small amounts of unconjugated dothiepin (unchanged drug) and northiaden were excreted in urine over a 72 hr period. More than 10% of the dose was excreted as conjugated dothiepin and less than 0.8% of the dose as conjugated northiaden. Conjugated dothiepin was thus found to be an important metabolite of dothiepin. Conjugated dothiepin and northiaden were hydrolyzed with beta-glucuronidase, and their hydrolysis inhibited with 1,4 saccharolactone. Conjugated dothiepin and northiaden were found to be a quaternary ammonium-linked glucuronide and a tertiary N-glucuronide, respectively.
... Plasma and blood concentrations of northiaden and blood concentrations of dothiepin S-oxide, two metabolites of dothiepin, were measured. Dothiepin S-oxide was the major metabolic reaching a peak level of 81 (34-150) ug/l at 5 (4-6) hr. In comparison, northiaden reached a peak concentration of only 10 (3-21) ug/l at 5 (4-9) hr. The mean half-life of elimination of dothiepin S-oxide was 19 (13-35) hr while that for northiaden was 33 (22-60) hr.
◉ Summary of Use during Lactation:Dothiepin 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 225 mg daily produce low levels in milk and breastfed infants' serum, and cause no adverse developmental consequences. Dothiepin would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months.
◉ Effects in Breastfed Infants:Eight women who were receiving dothiepin for depression breastfed (extent not stated) their infants aged 0.13 to 12.5 months of age. Maternal dosages ranged from 25 to 225 mg daily (0.38 to 4.5 mg/kg daily). None of the infants had any noticeable adverse reactions.
A retrospective, case-control study of 15 women who breastfed while taking dothiepin for depression compared the neurocognitive outcomes of their infants to those in a group of 15 depressed mothers who had not taken an antidepressant during breastfeeding and another 36 women without depression. The mothers in the dothiepin group had taken dosages of 150 to 225 mg daily for 4 to 134 weeks during breastfeeding. Infants had been exposed to dothiepin in breast milk at times from 3 to 152 weeks of age and were assessed at 3 to 5 years of age. There was no evidence of negative effects on the infants' development using a number of rating scales.
Two infants were breastfed for 7 to 18 weeks during maternal use of dothiepin. The drug was started when both infants were 8 weeks of age. One mother started with a dose of 50 mg daily that was increased to 100 mg daily; she took dothiepin for 33 weeks during breastfeeding. The other mother was taking 225 mg daily and nursed her infant for 25 weeks during breastfeeding. Formal testing indicated no adverse effects on infant development up to 30 months of age.
◉ Effects on Lactation and Breastmilk:Galactorrhea has been reported in one woman taking dothiepin.
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 dothiepin.
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.
来源:Drugs and Lactation Database (LactMed)
毒理性
相互作用
癫痫或心律不齐可能会在严重循环性抗抑郁药过量的患者中由氟马西尼诱发。/氟马西尼/
Seizures or arrhythmias may be precipitated /SRP: by flumazenil/ in patients with a serious cyclic antidepressant overdose. /Flumazenil/
来源:Hazardous Substances Data Bank (HSDB)
毒理性
解毒与急救
蛋白质的高度结合以及广泛的分布体积，往往排除了血液透析和血液灌流的潜在有用性。
The high degree of protein binding, together with the extensive volume of distribution, tends to preclude the potential usefulness of hemodialysis and hemoperfusion.
Following a dothiepin overdose leading to ventricular fibrillation and cardiac arrest, an adult was treated with intravenous sodium bicarbonate, dopamine, and lidocaine with hyperventilation. His condition remained unstable. One hour later, intravenous sodium chloride ... was given over 5 minutes. The blood pressure rose immediately; the QRS complexes narrowed and cardiac abnormalities became less frequent. Similar episodes of hypotension and cardiac abnormalities over the following days were reversed by rapid infusion of sodium chloride.
Treatment consists largely of gastric lavage and activated charcoal (either single or multiple doses). Although use of activated charcoal suggests a role in decreasing the half-life of dothiepin, other studies with TCAs show little or no such significant decrease in half-life.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
多塞平及其代谢物已在母乳中被检测到。婴儿每天的总平均暴露量大约占母亲多塞平剂量的4.4%。
Dothiepin and its metabolites have been detected in breast milk. The mean total daily infant exposure amounts to about 4.4% of the maternal dothiepin dosage.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
多塞平在胃肠系统中易被吸收。
Dothiepin is readily absorbed in the gastrointestinal tract.
The pharmacokinetics of dothiepin were evaluated in 9 depressed patients following a single oral dose of 75 mg. Blood and plasma concentrations of dothiepin and 2 major metabolites, northiaden and dothiepin S-oxide, were measured by gas chromatography/mass fragmentography. The mean (+/-SD) peak plasma concentrations of dothiepin were 49 +/- 27 ug/L at 3 +/- 1.2hr. Mean (+/-SD) estimates of other parameters were as follows: absorption half-life 1.1 +/- 1.1hr; distribution half-life 2.2 +/- 0.8 hr; elimination half-life 25 +/- 7hr; apparent volume of distribution 70 +/- 62 L/kg; and oral clearance 2.1 +/- 1.6 L/kg/hr. The mean (+/-SD) peak plasma concentration of dothiepin S-oxide was 125 +/- 43 ug/L at 3.5 +/- 1.3hr with an elimination half-life of 22 +/- 12 hr. The mean peak plasma concentration of northiaden was 6 +/- 3 ug/L at 4.5 +/- 1.1hr, with an elimination half-life of 31 +/- 12 hr. No significant differences were found in pharmacokinetic parameters compared with a previous study in 7 healthy volunteers. When data for the patients and healthy volunteers were combined (n = 16), pharmacokinetic parameters were not found to be affected by age. However, a significant difference was found between males and females for the elimination half-lives of dothiepin and northiaden, and for the apparent volume of distribution of dothiepin. The 24-hour blood/plasma concentrations of dothiepin and dothiepin S-oxide accurately predicted the steady-state concentrations obtained following 4 weeks' treatment with dothiepin 150 mg /at night/.
Twenty-seven healthy men received three single oral doses of 50-, 100-, and 150-mg dothiepin hydrochloride capsules in a three-way randomized, crossover dose-proportionality study. Plasma concentration-time profiles of dothiepin (1) were described by both one- and two-compartment models with first-order absorption. The total intrinsic clearance of dothiepin decreased from 165.5 to 121.1 L/hr as the dose was increased from 50 to 150 mg, but there was no significant effect on the terminal half-life (approximately 20 hr). Plasma concentration-time profiles of the three major metabolites of dothiepin, the S-oxide derivative of dothiepin, N,N-dimethyl[b,e]thiepin-delta 11(6 H), gamma-propylamine 5-oxide (2), the demethyl derivative, N-methyldibenzo[b,e]thiepin-delta 11(6 H), gamma-propylamine (3) and the demethyl S-oxide derivative N-methyldibenzo[b,e]thiepin-delta 11(6 H), gamma-propylamine 5-oxide (4), were described by a one-compartment model with apparent first-order formation. The AUC infinity values of the S-oxide 2 and the demethyl S-oxide 4 increased proportionally with dose. The dose proportionality of the demethyl metabolite 3 may not be ascertained from the data in this study. The corresponding half-lives of the three metabolites, which are dose independent, were approximately 24, 28, and 40 hr, respectively. /Dothiepin Hydrochloride/
[EN] IMIDAZOLIUM REAGENT FOR MASS SPECTROMETRY<br/>[FR] RÉACTIF D'IMIDAZOLIUM POUR SPECTROMÉTRIE DE MASSE
申请人：HOFFMANN LA ROCHE
公开号：WO2021234004A1
公开（公告）日：2021-11-25
The present invention relates to compounds which are suitable to be used in mass spectrometry as well as methods of mass spectrometric determination of analyte molecules using said compounds.
本发明涉及适用于质谱的化合物，以及利用该化合物进行分析物分子的质谱测定方法。
[EN] QUINAZOLINE DERIVATIVES, COMPOSITIONS, AND USES RELATED THERETO<br/>[FR] DÉRIVÉS DE QUINAZOLINE, COMPOSITIONS ET UTILISATIONS ASSOCIÉES
申请人：UNIV EMORY
公开号：WO2013181135A1
公开（公告）日：2013-12-05
The disclosure relates to quinazoline derivatives, compositions, and methods related thereto. In certain embodiments, the disclosure relates to inhibitors of NADPH-oxidases (Nox enzymes) and/or myeloperoxidase.
[EN] NMDA RECEPTOR MODULATORS AND USES THEREOF<br/>[FR] MODULATEURS DES RÉCEPTEURS NMDA ET UTILISATIONS DE CEUX-CI
申请人：CADENT THERAPEUTICS
公开号：WO2018119374A1
公开（公告）日：2018-06-28
Disclosed herein, in part, are heteroaromatic compounds and methods of use in treating neuropsychiatric disorders, e.g., schizophrenia and major depressive disorder. Pharmaceutical compositions and methods of making heteroaromatic compounds are provided. The compounds are contemplated to modulate the NMDA receptor.
[EN] ISOTOPE ENHANCED AMBROXOL FOR LONG LASTING AUTOPHAGY INDUCTION<br/>[FR] AMBROXOL À ISOTOPE AMÉLIORÉ POUR INDUCTION D'AUTOPHAGIE DURABLE
申请人：STC UNM
公开号：WO2018148113A1
公开（公告）日：2018-08-16
The present invention is directed to 13C and/or 2H isotope enhanced ambroxol ("isotope enhanced ambroxol") and its use in the treatment of autophagy infections, especially mycobacterial and other infections, disease states and/or conditions of the lung, such as tuberculosis, especially including drug resistant and multiple drag resistant tuberculosis. Pharmaceutical compositions comprising isotope enhanced amhroxol, alone or in combination with an additional bioactive agent, especially rifamycin antibiotics, including an additional autophagy modulator (an agent which is active to promote or inhibit autophagy), thus being useful against, an autophagy mediated disease state and/or condition), especially an antophagy mediated disease state and/or condition which occurs in the lungs, for example, a Mycobacterium infection. Chronic Obstructive Pulmonary Disease (COPD), asthma, pulmonary fibrosis, cystic fibrosis, Sjogren's disease and lung cancer (small cell and non-small cell lung cancer, among other disease states and/or conditions, especially of the lung. Methods of treating autophagy disease states and/or conditions, especially including autophagy disease states or conditions which occur principally in the lungs of a patient represent a further embodiment of the present invention. An additional embodiment includes methods of synthesizing compounds according to the present invention as otherwise disclosed herein.
[EN] TREATMENT OF AUTISM SPECTRUM DISORDERS, OBSESSIVE-COMPULSIVE DISORDER AND ANXIETY DISORDERS<br/>[FR] TRAITEMENT DE TROUBLES DU SPECTRE AUTISTIQUE, DE TROUBLES OBSESSIVO-COMPULSIFS ET DE TROUBLES DE L'ANXIÉTÉ
申请人：RUGEN HOLDINGS CAYMAN LTD
公开号：WO2018098128A1
公开（公告）日：2018-05-31
Disclosed are methods for treating NMDA receptor-mediated disorders by administering certain NR2B subunit-selective NMDA (N methyl-D aspartate) antagonists. NMDA receptor-mediated disorders include autism spectrum disorders, obsessive-compulsive disorder and anxiety disorders.
