Alprazolam is metabolized to less effective metabolites by various CYPs including CYP3A4, CYP3A5, CYP3A7, and CYP2C9. The majority of alprazolam metabolism is mediated by hydroxylation via CYP3As. 4-hydroxyalprazolam has 20% the binding affinity of the parent drug, alpha-hydroxyalprazolam has 66% the affinity, and the benzophenone metabolite has <1% the affinity.
Alprazolam, an anti-anxiety agent, is metabolized in rat and human liver by P4503A1 and P4503A4 respectively, to 4-hydroxy alprazolam (4-OHALP, pharmacologically less active) and alpha-hydroxy alprazolam (alpha-OHALP, pharmacologically more active). We examined P450 mediated metabolism of alprazolam by rat and human brain microsomes and observed that the relative amount of alpha-OHALP formed in brain was higher than liver. This biotransformation was mediated by a P450 isoform belonging to P4503A subfamily, which is constitutively expressed in neuronal cells in rat and human brain. The formation of larger amounts of alpha-OHALP in neurons points to local modulation of pharmacological activity in brain, at the site of action of the anti-anxiety drug. Since hydroxy metabolites of alprazolam are hydrophilic and not easily cleared through blood-CSF barrier, alpha-OHALP would potentially have a longer half-life in brain.
Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to two major metabolites in the plasma: 4-hydroxyalprazolam and a-hydroxyalprazolam. A benzophenone derived from alprazolam is also found in humans. Their half-lives appear to be similar to that of alprazolam. The plasma concentrations of 4-hydroxyalprazolam and a-hydroxyalprazolam relative to unchanged alprazolam concentration were always less than 4%. The reported relative potencies in benzodiazepine receptor binding experiments and in animal models of induced seizure inhibition are 0.20 and 0.66, respectively, for 4-hydroxyalprazolam and a-hydroxyalprazolam. Such low concentrations and the lesser potencies of 4-hydroxyalprazolam and a-hydroxyalprazolam suggest that they are unlikely to contribute much to the pharmacological effects of alprazolam. The benzophenone metabolite is essentially inactive.
Hepatic. Hydroxylated in the liver to α-hydroxyalprazolam, which is also active. This and other metabolites are later excreted in urine as glucuronides.
Route of Elimination: Alprazolam and its metabolites are excreted primarily in the urine.
Half Life: 6.3-26.9 hours
IDENTIFICATION AND USE: Alprazolam forms white to off-white, solid crystals. Classification: Psycholeptics, anxiolytics, and benzodiazepine derivatives. HUMAN EXPOSURE AND TOXICITY: Alprazolam, a widely used drug, has widespread, nonspecific depressant effects on the central nervous system, similar to other benzodiazepines. Alprazolam is used as an anxiolytic drug for generalized anxiety disorder and it has been reported to produce sedation and anterograde amnesia. Manifestations of alprazolam overdosage include somnolence, confusion, impaired coordination, diminished reflexes and coma. Death has been reported in association with overdoses of alprazolam by itself, as it has with other benzodiazepines. In addition, fatalities have been reported in patients who have overdosed with a combination of a single benzodiazepine, including alprazolam, and alcohol; alcohol levels seen in some of these patients have been lower than those usually associated with alcohol-induced fatality. Benzodiazepines can potentially cause fetal harm when administered to pregnant women. The newborn of a mother reporting alprazolam use during pregnancy presented with respiratory distress and clinical features consistent with neonatal withdrawal syndrome or neonatal sepsis of vertical transmission. Following ingestion of 10 mg of alprazolam, a 34 year old patient exhibited dangerous aggressive behavior. Five months later he presented with evidence of major depression. ANIMAL STUDIES: A retrospective study was conducted of 415 alprazolam ingestions in dogs: 238 suspected alprazolam toxicoses in dogs were evaluated. Clinical signs were ataxia/disorientation, depression, hyperactivity, vomiting, weakness, tremors, vocalization, tachycardia, tachypnea, hypothermia, diarrhea, and increased salivation that developed within 10-30 min post-ingestion. Other experiments in animals have indicated cardiopulmonary collapse can occur following massive intravenous doses of alprazolam. No evidence of carcinogenic potential was observed during 2 year bioassay studies of alprazolam in rats at doses up to 30 mg/kg/day and in mice at dose up to 10 mg/kg/day. Alprazolam produced no impairment of fertility in rats at doses up to 5 mg/kg/day. Altered behaviors in several mouse strains after prenatal exposure to alprazolam suggests a vulnerability of GABA-benzodiazepine receptor formation in fetal brain development. Mice offspring that were exposed prenatally to alprazolam demonstrated more individual rather than group activities, avoidance of open areas, and aggression in males. Alprazolam was not mutagenic in the rat micronucleus test at doses up to 100 mg/kg. Alprazolam also was not mutagenic in vitro in the DNA Damage/Alkaline Elution Assay or the Ames Assay. Alprazolam was also studied using Allium cepa test, where it induced chromosomal and cytological aberrations, especially nuclear alterations.
Benzodiazepines bind nonspecifically to benzodiazepine receptors BNZ1, which mediates sleep, and BNZ2, which affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. As benzodiazepine receptors are thought to be coupled to gamma-aminobutyric acid-A (GABA<sub>A</sub>) receptors, this enhances the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of the inhibitory neurotransmitter GABA to the site opens the chloride channel, resulting in a hyperpolarized cell membrane that prevents further excitation of the cell.
Alprazolam, like other benzodiazepines, is rarely associated with serum ALT or alkaline phosphatase elevations, and clinically apparent liver injury from alprazolam is extremely rare, considering the frequency of its use. There have been a few case reports of acute liver injury from alprazolam, and recurrence on reexposure has been reported. In alprazolam-related cases of acute liver injury, the latency has been within a few weeks and the typical pattern of liver enzyme elevations has been cholestatic or mixed (Case 1). The injury was usually mild-to-moderate in severity and self-limited in course. Fever and rash have not been described nor has autoantibody formation. Similar rare cases of self-limited, mild-to-moderate, cholestatic liver injury have been reported with other benzodiazepines including chlordiazepoxide, clonazepam, diazepam, flurazepam, lorazepam, and triazolam.
Alprazolam administered orally is rapidly absorbed in the gastrointestinal tract, reaching Cmax in about 1.8 (1-2) hours. Absorption is high, resulting in an oral bioavailability of 84-91%. A 1 mg oral dose results in a Cmax of 12-22 μg/L. The extended-release formulation of alprazolam (XANAX XR) has similar absorption, bioavailability, and pharmacokinetics as the standard release, with the exception that the Tmax is ~10 hours compared to 1-2 hours. Temporal dosing alters these parameters, with Cmax increasing by 30% and Tmax decreasing by one hour when dosed at night as opposed to in the morning. Food has an effect on alprazolam absorption; a high-fat meal up to two hours before dosing increases the Cmax by ~25% and either a reduction (food consumed immediately prior to dosing) or increase (food consumed after dosing) of ~1/3 in Tmax. Neither the AUC nor half-life are appreciably affected by eating.
Alprazolam is mainly eliminated in the urine. A large portion of the dose is eliminated as unmetabolized alprazolam. <10% of the dose is eliminated as alpha-hydroxy-alprazolam and 4-hydroxy-alprazolam.
A 0.8 mg oral dose of alprazolam had a clearance of 0.90 ± 0.21 mL/min/kg, which increased to 2.13 ± 0.54 mL/min/kg when coadministered with the strong CYP3A4 inducer carbamazepine. Other studies have demonstrated a clearance of 0.70-1.5mL/min/kg.
8-Chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines with substituents at C-4
摘要：
A series of 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines with substituents at C-4 was prepared and evaluated for antianxiety potential. It was found that substitution at this position generally decreased the activity in this series.
[EN] BENZAMIDE OR BENZAMINE COMPOUNDS USEFUL AS ANTICANCER AGENTS FOR THE TREATMENT OF HUMAN CANCERS<br/>[FR] COMPOSÉS BENZAMIDE OU BENZAMINE À UTILISER EN TANT QU'ANTICANCÉREUX POUR LE TRAITEMENT DE CANCERS HUMAINS
申请人：UNIV TEXAS
公开号：WO2017007634A1
公开（公告）日：2017-01-12
The described invention provides small molecule anti-cancer compounds for treating tumors that respond to cholesterol biosynthesis inhibition. The compounds selectively inhibit the cholesterol biosynthetic pathway in tumor-derived cancer cells, but do not affect normally dividing cells.
The invention relates to novel 3-amino pyrrolidine derivatives, as well as methods for modulating calcium channel activity and for treating conditions associated with calcium channel function. In particular, the compounds generally contain at least one benzhydril moiety, and are useful in treating conditions which benefit from blocking calcium ion channels.
[EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
申请人：GILEAD APOLLO LLC
公开号：WO2017075056A1
公开（公告）日：2017-05-04
The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.
[EN] S-NITROSOMERCAPTO COMPOUNDS AND RELATED DERIVATIVES<br/>[FR] COMPOSÉS DE S-NITROSOMERCAPTO ET DÉRIVÉS APPARENTÉS
申请人：GALLEON PHARMACEUTICALS INC
公开号：WO2009151744A1
公开（公告）日：2009-12-17
The present invention is directed to mercapto-based and S- nitrosomercapto-based SNO compounds and their derivatives, and their use in treating a lack of normal breathing control, including the treatment of apnea and hypoventilation associated with sleep, obesity, certain medicines and other medical conditions.
Chromenone derivatives useful for the treatment of neurodegenerative diseases
申请人：AxoGlia Therapeutics S.A.
公开号：EP2112145A1
公开（公告）日：2009-10-28
Compounds of general formula (I) and (II)
in which R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 have the meanings given in the specification, are useful in the treatment of neurodegenerative disease.
