Nortriptyline is metabolized via demethylation and hydroxylation in the liver followed by glucuronic acid conjugation. CYP2D6 plays a large role in nortriptyline metabolism, with contributions from CYP1A2, CYP2C19 and CYP3A4. The main active metabolite is 10-hydroxynortriptyline exists in both cis and a trans form, with the trans form is higher in potency. 10-hydroxynortriptyline is the most frequently found in the plasma. Most of the other metabolites are conjugated, and are less potent.
Biotransformation of amitriptyline to its demethylated product nortriptyline was studied in vitro with human liver microsomes from four different donors, preselected to reflect a range of metabolic rates. Reaction velocity versus substrate concn was consistent with a sigmoid Vmax model. Vmax varied from 0.42 to 3.42 nmol/mg/min, Km from 33 to 89 uM amitriptyline. Ketoconazole was a highly potent inhibitor of N-demethylation, with a mean Ki value of 0.11 + or - 0.013 uM ... whereas quinidine (up to 50 uM), a CYP2D6 inhibitor, and alpha-naphthoflavone (up to 5 uM), a CYP1A2 inhibitor only at low concn, showed no effect. All selective serotonin reuptake inhibitors tested had an inhibitory effect on the formation of nortriptyline, with mean Ki values of 4.37 (+ or - 3.38) uM for sertraline, 5.46 (+ or - 1.95) uM for desmethylsertraline, 9.22 (+ or - 3.69) uM for fluvoxamine, 12.26 (+ or - 5.67) uM for norfluoxetine, 15.76 (+ or - 5.50) uM for paroxetine, and 43.55 (+ or - 18.28) uM for fluoxetine. A polyclonal rabbit antibody against rat liver CYP3A1, in antibody/microsomal protein ratios varying from 1:1 to 10:1, inhibited N-demethylation of amitriptyline to an asymptotic max of 60%.
The metabolic disposition of the antidepressants and antipsychotics has been reported to be significantly influenced by the cytochrome P450 (CYP) 2D6 isozyme. The two most studied antidepressants are amitriptyline and imipramine. Amitriptyline conversion to nortriptyline and nortriptyline metabolism to its 10-hydroxymetabolite were shown to be influenced by the 2D6 isozyme.
The stability of amitriptyline, nortriptyline, desipramine and imipramine in formalin-fixed human liver tissue and formalin soln was investigated. The levels of the tricyclic and its primary demethylated metabolite in the frozen liver were determined and compared with levels obtained in the formalin-fixed liver and formalin soln in which the liver was stored. It was obvious that some methylation of the secondary amine, nortriptyline, to the corresponding tertiary amine, amitriptyline, and of desipramine to imipramine took place in the formalin environment. Nortriptyline was not detected in most cases, suggesting that it may degrade more rapidly than desipramine. There was no consistent ratio between the concn of the drug in the frozen liver tissue versus formalin-preserved tissue or versus formalin soln. The methylation rates of the secondary amines could not be quantitated. Storage of the liver tissue in formalin at room temp resulted in leaching of the drugs into the formalin soln. The drugs tested may be detected for up to 22 mo in the formalin-fixed liver and in the formalin medium.
IDENTIFICATION AND USE: Nortriptyline is a tricyclic antidepressant. HUMAN EXPOSURE AND TOXICITY: Symptoms of overdose/poisoning include the following: arrhythmias, bundle branch block, cardiac arrest, hypotension, circulatory collapse, mydriasis, blurred vision, tachycardia, vasodilation, urinary retention, decreased gastrointestinal motility, decreased bronchial secretions, dry mucous membranes and skin, hypothermia, respiratory depression, seizures, abnormal tendon reflexes, disorientation, agitation, myoclonic jerks, coma and pyramidal signs. A woman with chronic obstructive pulmonary disease receiving nortriptyline experienced depression of CO2 sensitivity and ventilatory load compensation with a concomitant increase in exercise tolerance with decreased dyspnea. In other words, nortriptyline demonstrated a depressant effect on ventilatory control. Nortriptyline increases the risk for sudden cardiac arrest in the general population, particularly in the presence of genetic and/or non-genetic factors that decrease cardiac excitability by blocking the cardiac sodium channel. Antidepressant have been shown to increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. ANIMAL STUDIES: Dogs receiving nortriptyline hydrochloride orally for twelve months tolerated as much as 20 mg/kg/day. However, a large oral dose (40 mg per kg daily) caused signs of depression and ataxia and, with continued treatment, death at the end of the first month. In chronic toxicity studies, rats tolerated a concentration of nortriptyline hydrochloride in the diet equivalent to 150 mg/kg/day for one year. Rats showed some growth retardation but no visceral damage. Nortriptyline was tested for genotoxicity using the somatic mutation and recombination test (SMART) in wing cells of Drosophila melanogaster. The drug was not genotoxic at concentrations up to 100 mM.
It is believed that nortriptyline either inhibits the reuptake of the neurotransmitter serotonin at the neuronal membrane or acts at beta-adrenergic receptors. Tricyclic antidepressants do not inhibit monoamine oxidase nor do they affect dopamine reuptake.
Liver test abnormalities have been reported to occur in up to 16% of patients being treated with tricyclic antidepressants, but elevations are uncommonly above 3 times the upper limit of normal. The aminotransferase abnormalities are usually mild, asymptomatic and transient, reversing even with continuation of medication. Rare instances of clinically apparent acute liver injury have been reported due to nortriptyline. The onset of jaundice is usually within 2 to 3 months of starting nortriptyline and the predominant enzyme pattern has been hepatocellular. Several acute instances of nortriptyline hepatotoxicity with marked elevations in serum aminotransferase levels and acute liver failure have been described. Signs and symptoms of hypersensitivity and autoimmunity are usually not present.
Nortriptyline is readily absorbed in the gastrointestinal tract with extensive variation in plasma levels, depending on the patient. This drug undergoes first-pass metabolism and its plasma concentrations are attained within 7 to 8.5 hours after oral administration. The bioavailability of nortriptyline varies considerably and ranges from 45 to 85%.
Nortriptyline and its metabolites are mainly excreted in the urine, where only small amounts (2%) of the total drug is recovered as unchanged parent compound. Approximately one-third of a single orally administered dose is excreted in urine within 24 hours. Small amounts are excreted in feces via biliary elimination.
The apparent volume of distribution (Vd)β, estimated after intravenous administration is 1633 ± 268 L within the range of 1460 to 2030 (21 ± 4 L/kg). Nortriptyline crosses the placenta and is found in the breast milk. It distributes to the heart, lungs, brain, and the liver.
The average plasma clearance of nortriptyline in a study of healthy volunteers was 54 L/h. The average systemic clearance of nortriptyline is 30.6 ± 6.9 L / h, within the range of 18.6 to 39.6 L/hour.
/MILK/ Nortriptyline is distributed into milk. Nortriptyline concentrations in milk appear to be similar to or slightly greater than those present in maternal serum.
[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.
[EN] METHYL OXAZOLE OREXIN RECEPTOR ANTAGONISTS<br/>[FR] MÉTHYLOXAZOLES ANTAGONISTES DU RÉCEPTEUR DE L'OREXINE
申请人：MERCK SHARP & DOHME
公开号：WO2016089721A1
公开（公告）日：2016-06-09
The present invention is directed to methyl oxazole compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.
4' SUBSTITUTED COMPOUNDS HAVING 5-HT6 RECEPTOR AFFINITY
申请人：Dunn Robert
公开号：US20080318941A1
公开（公告）日：2008-12-25
The present disclosure provides compounds having affinity for the 5-HT
6
receptor which are of the formula (I):
wherein R
1
, R
2
, R
5
, R
6
, B, D, E, G, Q, x and n are as defined herein. The disclosure also relates to methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.
Heterobicyclic compounds of Formula (I):
or a pharmaceutically-acceptable salt, tautomer, or stereoisomer thereof, as defined in the specification, and compositions containing them, and processes for preparing such compounds. Provided herein also are methods of treating disorders or diseases treatable by inhibition of PDE10, such as obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, Huntington's Disease, and the like.
Formula (I)的杂环化合物：
或其药用可接受的盐、互变异构体或立体异构体，如规范中所定义，并含有它们的组合物，以及制备这种化合物的方法。本文还提供了通过抑制PDE10来治疗由此可治疗的疾病或疾病的方法，如肥胖症、非胰岛素依赖型糖尿病、精神分裂症、躁郁症、强迫症、亨廷顿病等。
NAPHTHALENE-BASED INHIBITORS OF ANTI-APOPTOTIC PROTEINS
申请人：Pellecchia Maurizio
公开号：US20090105319A1
公开（公告）日：2009-04-23
Methods of using apogossypol and its derivatives for treating inflammation is disclosed. Also, there is described a group of compounds having structure A, or a pharmaceutically acceptable salt, hydrate, N-oxide, or solvate thereof are provided:
wherein each R is independently selected from the group consisting of H, C(O)X, C(O)NHX, NH(CO)X, SO
2
NHX, and NHSO
2
X, wherein X is selected from the group consisting of an alkyl, a substituted alkyl, an aryl, a substituted aryl, an alkylaryl, and a heterocycle. Compounds of group A may be used for treating various diseases or disorders, such as cancer.
