Amoxapine

Amoxapine is a tricyclic dibenzoxazepine (an N-aryl piperazine) which acts similarly to several other tricyclic antidepressants, amoxapine inhibits GLYT2a transport activity with IC50 of 92 μM.

Old drug new use--amoxapine and its metabolites as potent bacterial beta-glucuronidase inhibitors for alleviating cancer drug toxicity.[Pubmed:24780296]

Clin Cancer Res. 2014 Jul 1;20(13):3521-30.

PURPOSE: Irinotecan (CPT-11) induced diarrhea occurs frequently in patients with cancer and limits its usage. Bacteria beta-glucuronidase (GUS) enzymes in intestines convert the nontoxic metabolite of CPT-11, SN-38G, to toxic SN-38, and finally lead to damage of intestinal epithelial cells and diarrhea. We previously reported Amoxapine as a potent GUS inhibitor in vitro. To further understand the molecular mechanism of Amoxapine and its potential for treatment of CPT-11-induced diarrhea, we studied the binding modes of Amoxapine and its metabolites by docking and molecular dynamics simulation, and tested the in vivo efficacy on mice in combination with CPT-11. EXPERIMENTAL DESIGN: The binding of Amoxapine, its metabolites, 7-hydroxyAmoxapine and 8-hydroxyAmoxapine, and a control drug loxapine with GUS was explored by computational protocols. The in vitro potencies of metabolites were measured by Escherichia coli GUS enzyme and cell-based assay. Low-dosage daily oral administration was designed to use along with CPT-11 to treat tumor-bearing mice. RESULTS: Computational modeling results indicated that Amoxapine and its metabolites bound in the active site of GUS and satisfied critical pharmacophore features: aromatic features near bacterial loop residue F365' and hydrogen bond toward E413. Amoxapine and its metabolites were demonstrated as potent in vitro. Administration of low dosages of Amoxapine with CPT-11 in mice achieved significant suppression of diarrhea and reduced tumor growth. CONCLUSIONS: Amoxapine has great clinical potential to be rapidly translated to human subjects for irinotecan-induced diarrhea.

Crystal structure of a mixed solvated form of amoxapine acetate.[Pubmed:25878802]

Acta Crystallogr E Crystallogr Commun. 2015 Jan 10;71(Pt 2):139-41.

The mixed solvated salt 4-(2-chloro-dibenzo[b,f][1,4]oxazepin-11-yl)piperazin-1-ium acetate-acetic acid-cyclo-hexane (2/2/1), C17H17ClN3O(+).C2H3O2 (-).C2H4O2.0.5C6H12, crystallizes with one mol-ecule of protonated Amoxapine (AXPN), an acetate anion and a mol-ecule of acetic acid together with half a mol-ecule of cyclo-hexane. In the centrosymmetric crystal, both enanti-omers of the protonated AXPN mol-ecule stack alternatively along [001]. Acetate anions connect the AXPN cations through N-Hcdots, three dots, centeredO hydrogen bonding in the [010] direction, creating a sheet lying parallel to (100). The acetic acid mol-ecules are linked to the acetate anions via O-Hcdots, three dots, centeredO hydrogen bonds within the sheets. Within the sheets there are also a number of C-Hcdots, three dots, centeredO hydrogen bonds present. The cyclo-hexane solvent mol-ecules occupy the space between the sheets.

Simultaneous quantification of loxapine, loxapine N-oxide, amoxapine, 8-hydroxyloxapine and 7-hydroxyloxapine in human plasma using LC-MS/MS.[Pubmed:28152454]

J Chromatogr B Analyt Technol Biomed Life Sci. 2017 Mar 1;1046:87-97.

Loxapine is an antipsychotic medication used for the treatment of schizophrenia. In vivo, loxapine is metabolized to multiple metabolites. A high performance liquid chromatographic-tandem mass spectrometry (LC-MS/MS) method has been developed and validated for the determination of loxapine and 4 of its metabolites, loxapine N-oxide, Amoxapine (N-desmethyl loxapine), 8-hydroxyloxapine and 7-hydroxyloxapine, in human plasma to support regulated clinical development. During method development, several technical challenges such as poor chromatography, separation of structural isomers, and inadequate sensitivity were met and overcome. The final method utilized micro-elution solid phase extraction (SPE) to extract plasma samples (100muL), and the resulting extracts were analyzed using reversed phase LC-MS/MS using a turbo-ionspray interface in positive ionization mode with selected reaction monitoring (SRM). The method was fully validated according to the current regulatory guidance for bioanalysis over the calibration curve range 0.0500-50.0ng/mL for all analytes using 1/x(2)-weighted linear regression analysis. Based on three separate runs, the between-run precision and inter-day precision for all five analytes at all concentrations, including the LLOQ (lower limit of quantitation) quality control at 0.0500ng/mL, varied from 0.0% to 13.8%, while the accuracy ranged from 86.4% to 109.3% of nominal. The extraction recoveries of loxapine and the four metabolites were above 80%. Various forms of short-term and long-term stability were established in both solutions and matrix, including the stability of loxapine and the four metabolites in human plasma for up to 260days of storage at -20 degrees C. This method has been used to support a regulated clinical study, which included the successful execution of incurred sample reanalysis (ISR) testing. To the best of our knowledge, this is the first published methodology in which these five analytes were quantified with a single extraction and injection.

Randomized Crossover Trial of Amoxapine Versus Vitamin B12 for Retrograde Ejaculation.[Pubmed:28266821]

Int Braz J Urol. 2017 May-Jun;43(3):496-504.

OBJECTIVE: To compare the efficacy and safety of Amoxapine and vitamin B12 for treating retrograde ejaculation (RE). MATERIALS AND METHODS: Between May 2009 and November 2012, this open-label, randomized, crossover study enrolled 26 men suffering with RE at Department of Reproductive Medicine, Omori Hospital. Patients were randomly allocated into two groups (n=13 each). The Amoxapine-B12 group received Amoxapine (50 mg daily for 4 weeks, orally) followed (after a 1-week washout period) by vitamin B12 (500 mug three-times daily for 4 weeks). The B12-Amoxapine group received the opposite regimen. All pa-tients masturbated to ejaculation at least twice during each treatment period. The primary outcome was antegrade ejaculation of semen, as reported by the patient, on more than one occasion during either treatment period (defined as treatment success). Any adverse events were noted. Success rates were compared between treatments using Fisher's exact test. RESULTS: One patient (B12-Amoxapine group) withdrew for personal reasons (breakdown of marital relations); all other patients completed the study. Overall success rate was 88% (22/25). Success rate was higher for Amoxapine than for vitamin B12 (80%, 20/25 vs 16%, 4/25; P<0.0001). 18 patients were responsive to Amoxapine but not to vitamin B12, 2 patients were responsive to vitamin B12 but not Amoxapine, 2 patients were responsive to both drugs, and 3 patients had no response to either drug. One patient (4%) reported sleepiness and 2 (8%) reported constipation while receiving Amoxapine. No adverse events were reported during vitamin B12 treatment. CONCLUSIONS: Amoxapine may be an effective, safe and well-tolerated therapy for RE.

Amoxapine is a tetracyclic antidepressant of the dibenzoxazepine family, though it is often classified as a secondary amine tricyclic antidepressant.

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