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Background: Serotonin syndrome is a rare and potentially fatal adverse drug reaction caused by serotonergic drugs and is due to an increase in serotonin concentration or activation of the 5-HT receptor in the central nervous system. We analysed adverse events in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) data set to investigate the main drug classes related to reports of serotonin syndrome and the reporting risk in relation to age and sex. Methods: We analysed data from the FAERS database to evaluate the main drug classes related to reports of the serotonin syndrome, and the reporting risk in relation to age and sex. Results: We found 8,997 cases of serotonin syndrome; selective serotonin reuptake inhibitors (SSRIs) was the class of drugs with most reports, followed by opioids and other antidepressants. The highest Reporting Odds Ratios (ROR) for drug classes was for monoamine oxidase (MAO) inhibitors (45.99, 95% confidence interval (CI): 41.21–51.33) and SSRIs (32.66, 95% CI: 31.33–34.04), while the ten active substances with the highest ROR were moclobemide, isocarboxazid, oxitriptane, tranylcypromine, melitracen, phenelzine, linezolid, amoxapine, reboxetine and tryptophan; with values of ROR ranging from 44.19 (95% CI: 25.38–76.94) of tryptophan to 388.36 (95% CI: 314.58-479.46) of moclobemide. The ROR for the most commonly involved drugs was higher in the group of older adults (65 > years old), and higher in males. Conclusion: Prescribers need to be vigilant about drugs that can raise serotonin concentration or influence serotonergic neurotransmission, also when using drugs with less well-known risk for serotonin syndrome, like linezolid and triptans. [ABSTRACT FROM AUTHOR]

The objective of the present study is to design and formulate orodispersible tablets of Amoxapine using novel Co-processed superdisintegrants by employing direct compression method. Amoxapine is used to treat symptoms of depression. Amoxapine is a class II drug with high permeability and low solubility. There is a need to develop a formulation of Amoxapine that will enhance the bioavailability of the drug by decreasing the disintegration time. Thus improves patient compliance generate rapid response enhances bioavailability and also reduces dose of drug. In this study ODTs are prepared by direct compression method using novel super disintigrants in different proportions. The powder blend is subjected to pre compression parameters including bulk density, true density, tapped density, cars index, Hausner's ratio and angle of repose. The formulations are evaluated for weight variation, hardness, wetting time, water absorption test, disintegration time and in vitro dissolution studies and all formulations complies its Pharmacopoeial standards. The tablets are evaluated and the results compared for all four super disintigrants revealed cross povidone to be the most efficious super disintigrants to formulate mouth dissolving tablets of Naproxen sodium as suggested by the dispersion time, disintegration time and drug dissolution profiles. [ABSTRACT FROM AUTHOR]

GABAA receptors, members of the pentameric ligand-gated ion channel superfamily, are widely expressed in the central nervous system and mediate a broad range of pharmaco-toxicological effects including bidirectional changes to seizure threshold. Thus, detection of GABAA receptor-mediated seizure liabilities is a big, partly unmet need in early preclinical drug development. This is in part due to the plethora of allosteric binding sites that are present on different subtypes of GABAA receptors and the critical lack of screening methods that detect interactions with any of these sites. To improve in silico screening methods, we assembled an inventory of allosteric binding sites based on structural data. Pharmacophore models representing several of the binding sites were constructed. These models from the NeuroDeRisk IL Profiler were used for in silico screening of a compiled collection of drugs with known GABAA receptor interactions to generate testable hypotheses. Amoxapine was one of the hits identified and subjected to an array of in vitro assays to examine molecular and cellular effects on neuronal excitability and in vivo locomotor pattern changes in zebrafish larvae. An additional level of analysis for our compound collection is provided by pharmacovigilance alerts using FAERS data. Inspired by the Adverse Outcome Pathway framework, we postulate several candidate pathways leading from specific binding sites to acute seizure induction. The whole workflow can be utilized for any compound collection and should inform about GABAA receptor-mediated seizure risks more comprehensively compared to standard displacement screens, as it rests chiefly on functional data. [ABSTRACT FROM AUTHOR]

Background: Amoxapine is a second-generation tricyclic antidepressant with a greater seizure risk than other antidepressants. If administered in large amounts, amoxapine can cause severe toxicity and death. Therefore, it is necessary to terminate seizures immediately if amoxapine toxicity occurs. However, intractable seizures often occur in these patients. We describe a case of intractable seizures caused by amoxapine poisoning, in which intravenous lipid emulsion (ILE) was used successfully.Case Report: A 44-year-old woman with a history of depression ingested 3.0 g of amoxapine during a suicide attempt. Although she was initially treated with intravenous diazepam, her seizures persisted. Levetiracetam and phenobarbital were then administered, but seizures persisted. Hence, ILE was injected for over 1 min. At 2 min after ILE administration, the patient's status seizures ceased. Recurrence of seizures was observed 30 min after ILE, and the seizures disappeared after re-administration of ILE. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: ILE may be effective in amoxapine intoxication. Emergency physicians may consider ILE as an adjunctive therapy for amoxapine poisoning with a high mortality rate. ILE should be implemented carefully with monitoring of total dosage and adverse events. [ABSTRACT FROM AUTHOR]

Drug-induced enteropathy is often associated with the therapeutic use of certain glucuronidated drugs. One such drug is mycophenolic acid (MPA), a well-established immunosuppressant of which gastrointestinal adverse effects are a major concern. The role of bacterial β-glucuronidase (β-G) from the gut microbiota in MPA-induced enteropathy has recently been discovered. Bacterial β-G hydrolyzes MPAG, the glucuronide metabolite of MPA excreted in the bile, leading to the digestive accumulation of MPA that would favor in turn these adverse events. We therefore hypothesized that taming bacterial β-G activity might reduce MPA digestive exposure and prevent its toxicity. By using a multiscale approach, we evaluated the effect of increasing concentrations of MPA on intestinal epithelial cells (Caco-2 cell line) viability, proliferation, and migration. Then, we investigated the inhibitory properties of amoxapine, a previously described bacterial β-G inhibitor, by using molecular dynamics simulations, and evaluated its efficiency in blocking MPAG hydrolysis in an Escherichia coli -based β-G activity assay. The pharmacological effect of amoxapine was evaluated in a mouse model. We observed that MPA impairs intestinal epithelial cell homeostasis. Amoxapine efficiently blocks the hydrolysis of MPAG to MPA and significantly reduces digestive exposure to MPA in mice. As a result, administration of amoxapine in MPA-treated mice significantly attenuated gastrointestinal lesions. Collectively, these results suggest that the digestive accumulation of MPA is involved in the pathophysiology of MPA-gastrointestinal adverse effects. This study provides a proof-of-concept of the therapeutic potential of bacterial β-G inhibitors in glucuronidated drug-induced enteropathy. [Display omitted] • Digestive accumulation of mycophenolic acid favors gastrointestinal adverse effects. • The bacterial β-G inhibitor, amoxapine, prevents mycophenolate-induced enteropathy. • Bacterial β-glucuronidase inhibitors as add-on therapy in drug-induced enteropathy. [ABSTRACT FROM AUTHOR]

• Experimentally as well as theoretically in-depth, complexes are thoroughly characterized. • Various thermodynamic parameters were assessed through the application of spectroscopic methods. • Theoretical study via DFT predicts inclusion phenomena. This investigation involved the inclusion of the antidepressant drug amoxapine (AXP) and gamma-cyclodextrin host molecules using a co-precipitation technique to produce a supramolecular complex. The objective was to acquire a more profound comprehension of the construction and long-lasting nature of the inclusion complex (IC) on a physical scale. The resultant hybrid underwent thorough characterization employing various methods including 1H nuclear magnetic resonance (1H NMR), electrospray ionization mass spectrometry (ESI-MS), and UV-VIS spectroscopy. A stoichiometric ratio of 1:1 was determined through Job's plot, and binding constant values were obtained using UV-VIS spectroscopic titrations with the assistance of the Benesi-Hildebrand technique. The experimental observations were supported by the ESI-MS data. The inclusion complexation was validated through a meticulous analysis of the results from molecular modeling. The preliminary computational screening via DFT revealed the stability of the amoxapine- γ cyclodextrin IC based on adsorption energy calculation. Furthermore, the inclusion complexation phenomenon was confirmed by the outcomes of 1H NMR and ESI-MS studies. The computational findings aligned consistently with the experimental data, providing substantiation for the encapsulation of amoxapine within γ -cyclodextrin. [Display omitted] [ABSTRACT FROM AUTHOR]

In the event of an overdose, the pharmacokinetics of the drug may be altered, resulting in an unexpectedly rapid increase in blood and tissue drug concentrations. Because central nervous system (CNS)-acting drugs are the major cause of hospitalization for overdose, brain concentrations, which are closely related to the development of acute psychotropic symptoms, would be important. However, due to the lack of an appropriate model for overdose, it is difficult to predict the CNS symptoms of patients with acute poisoning. To clarify the toxicokinetics during intoxication with CNS-acting drugs, we investigated the relationship between the dose and concentrations in the blood and brain in mice. Therapeutic or toxic doses of phenobarbital, flunitrazepam, imipramine, and amoxapine were administered intraperitoneally to mice. Serum and extracellular fluid of the brain were collected up to 24 hr after administration and analyzed using LC-MS/MS to determine the pharmacokinetic parameters in the serum and brain. A comparison of the four psychotropic drugs showed that the toxicokinetics of amoxapine in the blood and brain are clearly different from others, with the brain concentrations being specifically highly susceptible to increase during dose escalation. These results are consistent with the CNS-related symptoms observed in amoxapine overdose. Therefore, the methodology of the current study could be useful for predicting CNS toxicity during psychotropic drug poisoning. [ABSTRACT FROM AUTHOR]

【Purpose】 To evaluate the treatment outcome of amoxapine for ejaculatory disorder, retrospectively. 【Patients and methods】 Patients were 17 men (age 38.4 ± 5.2 y) complaining with infertility or ejaculation disorder who received amoxapine (25-75 mg/day) under the diagnosis of retrograde ejaculation or emission less. Changes of semen analysis findings before and after treatment were examined. When the semen volume increased after therapy, it was considered to be effective. 【Results】 The efficacy rate was 78.6%. Before and after treatment with amoxapine, semen volume increased significantly from 0.29 ± 0.31 ml to 1.23 ± 1.56 ml, sperm concentration did from 19.5 ± 34.7 × 106 /ml to 99.3 ± 172.7 × 106 /ml, and total sperm count did from 7.83 ± 14.0 × 106 to 94.8 ± 149.7 × 106, respectively. There were 3 spontaneous pregnancies and 2 pregnancies due to assisted reproductive technology. All 5 pregnancies resulted in delivery. 【Conclusion】 It is suggested that amoxapine is an effective drug for ejaculation disorder and may not only increase ejaculation volume but also improve sperm concentration and total sperm count. [ABSTRACT FROM AUTHOR]

We report successful spontaneous pregnancy and delivery in two cases of complete retrograde ejaculation treated with amoxapine. [Case 1] A 36-years-old man. He became unabled to ejaculate after sigmoidectomy for dolichocolon and proctopexy for rectal prolapse. With diagnosis of complete retrograde ejaculation caused by those surgery, oral amoxapine 25mg daily was started. Oral amoxapine led to increase semen volume ejaculated antegradely to normal. While several therapeutic courses of assisted reproductive technique failed, he continued to be treated with amoxapine. After taking amoxapine for 6 years, his wife got spontaneous pregnancy and delivered a baby. [Case2] A 30-years-old man. Although he had normal orgasm, he had never ejaculated antegradely. He visited our hospital with hope of having a baby. Taking amoxapine 25mg daily induced antegrade ejaculation, but ejaculated semen volume was low (0.1-0.6ml). One year after treatment using Hochu-ekki-to with amoxapine, his wife got spontaneous pregnancy and delivered a baby. [ABSTRACT FROM AUTHOR]

Non-typhoidal Salmonella ingeniously scavenges energy for growth from tyramine (TYR) and d-glucuronic acid (DGA), both of which occur in the host as the metabolic byproducts of the gut microbial metabolism. A critical first step in energy scavenging from TYR and DGA in Salmonella involves TYR-oxidation via TYR-oxidoreductase and production of free-DGA via β-glucuronidase (GUS)-mediated hydrolysis of d-glucuronides (conjugated form of DGA), respectively. Here, we report that Salmonella utilizes TYR and DGA as sole sources of energy in a serotype-independent manner. Using colorimetric and radiometric approaches, we report that genes SEN2971, SEN3065, and SEN2426 encode TYR-oxidoreductases. Some Salmonella serotypes produce GUS, thus can also scavenge energy from d-glucuronides. We repurposed phenelzine (monoaminoxidase-inhibitor) and amoxapine (GUS-inhibitor) to inhibit the TYR-oxidoreductases and GUS encoded by Salmonella, respectively. We show that phenelzine significantly inhibits the growth of Salmonella by inhibiting TYR-oxidoreductases SEN2971, SEN3065, and SEN2426. Similarly, amoxapine significantly inhibits the growth of Salmonella by inhibiting GUS-mediated hydrolysis of d-glucuronides. Because TYR and DGA serve as potential energy sources for Salmonella growth in vivo, the data and the novel approaches used here provides a better understanding of the role of TYR and DGA in Salmonella pathogenesis and nutritional virulence.

This communication details the synthesis, evaluation of photophysical properties, and cellular imaging studies of cyanine chromophore based fluorescent dye 1 as a selective imaging agent for mitochondria. [ABSTRACT FROM AUTHOR]

The mixed solvated salt 4-(2-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-1-ium acetate–acetic acid–cyclohexane (2/2/1), C17H17ClN3O+·C2H3O2−·C2H4O2·0.5C6H12, crystallizes with one molecule of protonated amoxapine (AXPN), an acetate anion and a molecule of acetic acid together with half a molecule of cyclohexane. In the centrosymmetric crystal, both enantiomers of the protonated AXPN molecule stack alternatively along [001]. Acetate anions connect the AXPN cations through N—H...O hydrogen bonding in the [010] direction, creating a sheet lying parallel to (100). The acetic acid molecules are linked to the acetate anions via O—H...O hydrogen bonds within the sheets. Within the sheets there are also a number of C—H...O hydrogen bonds present. The cyclohexane solvent molecules occupy the space between the sheets.

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 (100 μL), 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 0.0500–50.0 ng/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 0.0500 ng/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 260 days of storage at −20 °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. [ABSTRACT FROM AUTHOR]

We attempted the simultaneous determination of 5 drugs, mirtazapine, sertraline, chlorpromazine, amoxapine and zolpidem, detected in a gas chromatography-mass spectrometry screening test in an autopsy case. The solid-phase extraction of the analytes from biological samples was achieved using Oasis®HLB cartridges (Waters, Milford, MA, USA). Gas chromatography was performed on a HP-5MS fused silica capillary column (30 m × 0.25 mm i.d., 0.25 μm film thickness, Agilent Technologies). The mass spectrometer was operated with an electron energy of 70 eV in electron impact mode. The qualitative and quantitative analyses were performed in full-scan mode and the selected ion monitoring mode, respectively. The total ion chromatogram showed good separation of these drugs. Linear graphs were obtained with good correlation coefficients for these drugs from 0.001 to 2.0 μg/mL (r2 = 0.9909- 0.9986) using imipramine-d6 as an internal standard. The recoveries of these drugs were found to be 62.8-88.0% in spiked whole blood. Mirtazapine, sertraline, chlorpromazine, amoxapine and zolpidem were found in post-mortem samples of the deceased at concentrations of 2.67, 0.07, 0.25, 0.32 and 0.68 mg/mL, respectively. The concentration of mirtazapine was within the lethal level and those of amoxapine and zolpidem were within the toxic level. We diagnosed that the cause of death was acute multiple drug poisoning. The simple and practical procedure used in this study is useful for the simultaneous determination of psychotropic drugs of various types in post-mortem biological samples. [ABSTRACT FROM AUTHOR]

The active metabolite of the chemotherapeutic irinotecan, SN-38, is detoxified through glucuronidation and then excreted into the gastrointestinal tract. Intestinal bacteria convert the glucuronidated metabolite back to the toxic SN-38 using β-glucuronidase (GUS), resulting in debilitating diarrhea. Inhibiting GUS activity may relieve this side effect of irinotecan. In this study, we sought to determine whether any known drugs have GUS inhibitory activity. We screened a library of Food and Drug Administration–approved drugs with a cell-free biochemical enzyme assay using purified bacterial GUS. After triage, five drugs were confirmed to inhibit purified bacterial GUS. Three of these were the monoamine oxidase inhibitors nialamide, isocarboxazid, and phenelzine with average IC50 values for inhibiting GUS of 71, 128, and 2300 nM, respectively. The tricyclic antidepressant amoxapine (IC50 = 388 nM) and the antimalarial mefloquine (IC50 = 1.2 µM) also had activity. Nialamide, isocarboxazid, and amoxapine had no significant activity against purified mammalian GUS but showed potent activity for inhibiting endogenous GUS activity in a cell-based assay using living intact Escherichia coli with average IC50 values of 17, 336, and 119 nM, respectively. Thus, nialamide, isocarboxazid, and amoxapine have potential to be repurposed as therapeutics to reduce diarrhea associated with irinotecan chemotherapy and warrant further investigation for this use. [ABSTRACT FROM PUBLISHER]

Abstract: Loxapine represents an interesting example of old “new” drug and is recently drawing attention for its novel inhalation formulation for the treatment of both psychiatric and non-psychiatric disorders. It is extensively metabolized to several active metabolites with diverging pharmacological properties. To further pursue the contribution of metabolites to the overall outcome after loxapine administration, quantification of both loxapine and its active metabolites is essential. The current study developed a rapid liquid chromatography–tandem mass spectrometry (LC–MS/MS) method for the simultaneous quantification of loxapine and its five metabolites (amoxapine, 7-hydroxy-loxapine, 8-hydroxy-loxapine, 7-hydroxy-amoxapine and 8-hydroxy-amoxapine) in rat brain tissues, plasma and cerebrospinal fluid (CSF). By evaluating the effects of perchloric acid and methanol on analyte recovery, the extraction methods were optimized and only small amounts of sample (100μl for plasma and less than 100mg for brain tissue) were required. The lower limits of quantification (LLOQs) in brain tissue were 3ng/g for loxapine and amoxapine and 5ng/g for the four hydroxylated metabolites of loxapine. The LLOQs were 1ng/ml for loxapine and amoxapine and 2ng/ml for the four hydroxylated metabolites in plasma, and 10ng/ml for all analytes in CSF. The developed method was applied to a pharmacokinetic study on rats treated with a low-dose loxapine by oral administration. Four hours after loxapine dosing, high levels of 7-hydroxy-loxapine were found throughout the ten brain regions examined (68–124ng/g), while only trace amount of loxapine was measured in brain (<5ng/g) and plasma (<3ng/ml). The method provides a useful tool for both preclinical and clinical investigations on the dispositions of loxapine and its metabolites, which would help to elucidate their roles in neurotherapeutics. [Copyright &y& Elsevier]

Background: Although tricyclic antidepressants amoxapine is proposed to target 5-HT and D2 receptors, very few studies have addressed the effect of amoxapine on molecular and cellular mechanisms via receptor pathways. In this study, we test the effect of amoxapine on rat cerebellar granule neurons (CGNs) to address this possibility. Methods: CGNs cell culture, whole-cell current recording using a patch-clamp technique, western blot and non-radioactive detection analysis of phosphorylated protein kinase A (PKA) were used. Results: Amoxapine inhibits delayed rectifier potassium (IK) current in a dose-dependent manner and modulates inactivation properties in CGNs. Those effects were not eliminated by preincubation with 5-HT or 5-HT receptor antagonists, but abolished by dopamine and D1/D5 receptor antagonists. Application of GTPγ-S and inhibitor of the Gs signalling cascade abolished the amoxapine-induced effect on IK. The application of forskolin or dibutyryl-cAMP mimicked the inhibitory effect of amoxapine on IK. Western blotting for phosphorylated PKA revealed that amoxapine significantly increased the intracellular levels of phosphorylated PKA, a marker of PKA activation. Conclusion: Amoxapine inhibits IK currents in rat CGNs via cAMP/PKA-dependent pathways, as in mouse cortical neurons we reported earlier, but that involves D1-like receptors instead of 5-HT receptors. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background The use of propofol as treatment of toxin-induced seizures is unclear. The goal of this study was to characterize the use of propofol for toxin-related seizures as reported to a statewide poison system. Methods This study was a retrospective review of the electronic records from a poison control system from 2009 to 2012. Inclusion criteria were patient age (≥ 18 yrs) and cases coded with 'seizure' that contained the term 'propofol.' The age, sex, reported toxin(s) involved, recurrence of seizure activity following/during propofol use, and mortality were extracted. Results Records review identified 235 poisoning cases, all of which involved adjunctive therapy with propofol. The age range was 18-82 years (53% female). A total of 155 different toxins were identified. Recurrent seizures occurred in 15.7% (n=37) of cases following propofol administration. The mortality rate was 6.8% (n=16) in cases with known outcomes. Conclusions Propofol is being used as an anticonvulsant in poisoned patients and appears to have some utility as an adjunct in terminating toxin-related seizures once airway control has been established. Less clear, however, is at what point propofol therapy should be initiated. Prospective controlled studies are warranted to identify the role of propofol in controlling toxin-induced seizures. [ABSTRACT FROM AUTHOR]

Abstract: A 43-year-old woman was found dead in a car in the supine position. She had been suffering from depression for 2 years and hesitation wounds on the left forearm and wrist were observed. On microscopic examination, pulmonary congestion and edema were observed with heart failure cells in many alveoli, thereby suggesting not only acute but also chronic heart failure. Drug screening in the blood by gas chromatography–mass spectrometry (GC–MS) revealed the presence of amoxapine and levomepromazine, and their concentrations in tissues were determined by GC–MS with three-step solvent extraction followed by acetylation. The concentration of amoxapine in the blood and liver was 0.86–1.77 and 18.76μg/ml, respectively; the levels were much higher than the therapeutic level but did not reach the lethal level. The concentrations of levomepromazine in tissues were within the therapeutic level. Based on the pathological and toxicological findings, the cause of death was determined to be amoxapine poisoning on the basis of chronic heart failure due to the chronic use of psychotropic drugs. [Copyright &y& Elsevier]

Abstract: A pharmacological characterization of glycine transport was performed in the rat retina at different postnatal ages. The uptake of 3H-glycine increased during the first 2 weeks of postnatal age, reaching maximum values at 12 days; then it decreased sharply to the adult values. We found a Na+-dependent and high-affinity transport system with a K m of 100μM. The Na+ Hill coefficient for glycine uptake was 1.76±0.07. Although glycine uptake was insensitive to staurosporine and phorbol ester, it was reduced 40–50% by sarcosine and ALX5407. Besides, amoxapine inhibited glycine uptake by 40 and 70% in adult and immature retina, respectively. These results suggest that the Glyt1 transporter was concentrated in the nerve terminals. In addition to the presence of Glyt1 in the retina, our results provided evidence of the occurrence of Glyt2 and/or another isoform of glycine transporter, which might have had a role in the retina development. [Copyright &y& Elsevier]

Amoxapine is marketed as an antidepressant. However, its invitro profile, receptor occupancy and preclinical effects are very similar to atypical antipsychotics. Amoxapine has also shown efficacy as an atypical antipsychotic in open trials. The objective of this study was to compare the antipsychotic and side effect profile of amoxapine and risperidone in a randomised assignment, standardized dosing, double-blind trial of acutely psychotic patients with schizophrenia. A total of 48 schizophrenic patients were enrolled and randomized in a double-blind 6-week trial to receive either risperidone (up to 5 mg/day) or amoxapine (up to 250 mg/day). Positive, negative, affective symptoms and motor side effects were measured using standardized weekly assessments. Prolactin levels were also determined at baseline and at the end of the study. A total of 39 patients (amoxapine, n=22; risperidone, n=21) completed the trial. Both pharmacological treatments, amoxapine 228.0 mg/day (SD=34.6) and risperidone 4.5 mg/day (SD=0.7), showed equivalent improvement in positive, negative, and depressive symptoms. Amoxapine was associated with less EPS and less prolactin elevation than risperidone. These data support previous reports about the efficacy of amoxapine as an atypical antipsychotic. Since amoxapine is off-patent, it may be a valuable low-cost alternative to new atypical antipsychotics, particularly in low-income countries where the majority of the patients are still treated with typical antipsychotics.Neuropsychopharmacology (2005) 30, 2236–2244. doi:10.1038/sj.npp.1300796; published online 8 June 2005 [ABSTRACT FROM AUTHOR]

Objective: Amoxapine is marketed as an antidepressant. However, its receptor occupancy, in vitro and in vivo, and its effects in pre-clinical models are very similar to atypical antipsychotics. To examine if this leads to an atypical antipsychotic effect in the clinical context, the authors examined the antipsychotic and side-effect profile of amoxapine in acutely psychotic patients with schizophrenia. Methods: Seventeen patients were enrolled and 15 completed a prospective open-label 6-week study of amoxapine starting with a fixed-starting dose (150 mg/h) with standardized titration up to 250 mg/h, if required. Positive, negative, affective symptoms and side-effects were monitored using standardized weekly assessments. Results: Amoxapine (median final dose 210 mg/h) was well-tolerated and showed significant improvement in positive and negative symptoms (both p<0.001), with a trend towards improvement in mood symptoms and no treatment-emergent extrapyramidal side-effects, akathisia or weight gain. Prolactin elevation was observed. Conclusion: These clinical data lend support to the pre-clinical suggestions that amoxapine may be an atypical antipsychotic. Given its lack of weight gain and that it is considerably less expensive than current options, amoxapine could be a valuable alternative for some patients. These considerations strongly call for more systematic, double-blind studies of amoxapine as an atypical antipsychotic. [Copyright &y& Elsevier]

Amoxapine, a tricyclic antidepressant, is widely used by psychiatrists. While overdose of tricyclic antidepressants is known to be dangerous and potentially fatal (causing hypotension, arrhythmia, convulsions, respiratory failure, and other serious complications), overdose of amoxapine can cause other problems, and metabolic acidosis, seizures, neuroleptic malignant syndrome, and arrhythmia have been reported. This report describes the case of a patient who developed rhabdomyolysis and acute renal failure following amoxapine overdose. Continuous hemofiltration was instituted twice, and he recovered without sequelae; this suggests the effectiveness of continuous hemofiltration and its possibilities in the treatment of amoxapine overdose and acute renal failure due to rhabdomyolysis. [ABSTRACT FROM AUTHOR]

This study was designed to evaluate the antidepressant activity of various antidepressants using the learned helplessness test (LH) or the forced swimming test (FS) in rats. Repeated treatment of the tricyclic antidepressants imipramine (10 mg/kg, p.o.), clomipramine (0.625 mg/kg, p.o.), amitriptyline (10 mg/kg, p.o.) and amoxapine (20 mg/kg, p.o.) reduced the number of escape failures in the LH group, respectively. Repeated treatment of an atypical antidepressant, mianserin (2.5 and 5 mg/kg, p.o.), and one of the selective serotonin reuptake inhibitors (SSRI), fluvoxamine (1.25 mg/kg, p.o.), also reduced the number of escape failures in the LH group. In the FS, repeated treatment of imipramine (5, 10 mg/kg, p.o.), amitriptyline (5, 10 mg/kg, p.o.) and mianserin (10 mg/kg) significantly decreased the duration of immobility time. On the other hand, repeated treatment of amoxapine (5–20 mg/kg), clomipramine (0.1325–1.25 mg/kg, p.o.) and fluvoxamine (0.3125–1.25 mg/kg, p.o.) failed to decrease the duration of immobility time in the FS group. In conclusion, these results suggest that the LH group is sensitive to agents with a variety of antidepressant properties compared to the FS group in rats. [ABSTRACT FROM AUTHOR]

Depression is common in patients with advanced, irreversible disease, but it is not normal. Many drugs and morbid states have been associated with depression. Psychotherapy, cognitive therapy, and electroconvulsive therapy, as well as pharmacotherapy may be helpful. The use of antidepressants and psychostimulants to manage depression in terminally ill patients is reviewed. Evaluation instruments that have been used to assess depression in this population are described. Some open research questions are listed. A treatment algorithm, evidence tables, and drug therapy tables which include drug costs are presented. [ABSTRACT FROM PUBLISHER]

Twenty-eight depressed patients receiving amoxapine with ages ranging from 21 to 68 years (male 12, female 16) were studied in order to clarify the age effect on plasma levels of amoxapine and its major active metabolite, 8-OH amoxapine. Plasma amoxapine levels were determined by both radioreceptor assay (RRA) and gas liquid chromatography (GLC). Plasma levels of 8-OH amoxapine were also determined by GLC. A highly significant correlation was found for plasma levels of amoxapine determined by RRA and GLC (r = 0.88, p < 0.001). There was no significant correlation between the amoxapine daily dose (mg/kg) and its plasma levels determined either by RRA or GLC. The ratios of plasma amoxapine level by RRA and GLC to daily dose significantly increased with advancing and (p < 0.05) and a significant positive correlation was also found between the ratio of plasma of 8-OH amoxapine to daily dose and the age of the patients (p < 0.01) suggesting that the plasma 8-OH amoxapine levels were more strongly affected by age than the parent drug. These results indicate that the metabolism of amoxapine in the liver decreases with age as well as that of other tricyclic antidepressants reported previously. The higher correlation of 8-OH amoxapine with patient's age may be mainly due to its renal excretion which may also decrease with age. [ABSTRACT FROM AUTHOR]

We showed previously that antidepressants inhibit GABA-stimulated [sup 36] Cl[sup –] uptake in rat cerebral cortex. In this study Schild analysis was used to determine if antidepressants are competitive antagonists or allosteric modulators at GABA[sub A] receptors. GABA concentration-response curves for [sup 36] Cl[sup –] uptake in rat cerebral cortex were generated in the absence or presence of different concentrations of the following antidepressants: amitriptyline, amoxapine, mianserin, and also the GABA[sub A] receptor antagonist, bicuculline. The pA[sub 2] values for amitriptyline, amoxapine, mianserin, and bicuculline were 4.2 ± 0.2, 5.5 ± 0.3, 4.4 ± 0.1 and 6.2 ± 0.6, respectively. The respective Schild slope values were 0.7 ± 0.1, 0.6 ± 0.03, 0.7 ± 0.2 and 1.0 ± 0.3. All slope values for antidepressants differed from unity. The maximum effect produced by GABA to stimulate chloride influx was decreased by both antidepressants and bicuculline. It is concluded that neither the antidepressants studied nor bicuculline are pure competitive GABA antagonists at the GABA[sub A] receptor-chloride-ionophore complex in the rat cerebral cortex. [ABSTRACT FROM AUTHOR]

The effects of amoxapine on membrane potentials and membrane currents of rabbit sinoatrial node were studied using the double microelectrode voltage clamp method. Amoxapine (> 1 μmol·litre−1) decreased the heart rate and the maximum rate of rise and the rate of diastolic depolarisation in a dose dependent manner. Above 3 μmol·litre−1, amoxapine also decreased the action potential amplitude and prolonged the action potential duration at half amplitude. These electrophysiological changes induced by amoxapine were relatively reduced in a high calcium medium (extracellular calcium concentration 4.0 mmol·litre−1). In voltage clamp experiments amoxapine depressed the slow inward current, the time dependent potassium current, and the hyperpolarisation activated inward current. The major effect, however, was considered to be a reduction of the slow inward current. It is concluded that amoxapine produced an inhibitory action on the electrical activity of sinoatrial node, and this action is mainly explained by an inhibition of calcium influx through the cell membrane. [ABSTRACT FROM PUBLISHER]

We have studied the effects of single oral doses of amoxapine (100 mg and 200 mg), amitriptyline (50 mg and 100 mg), and placebo on some autonomic functions in ten healthy volunteers, using a balanced double-blind crossover design. Amitriptyline significantly reduced salivation and it significantly attenuated both miosis evoked by locally applied pilocarpine and sweat secretion evoked by locally applied carbachol. Amoxapine did not significantly alter any of these measures. Neither treatment significantly altered the pupillary light reflex (latency, amplitude, or 75% recovery time). Resting pupil diameter was significantly reduced by the higher dose of amoxapine but was not affected by the other treatments. The higher dose of amoxapine significantly increased supine systolic blood pressure, but did not affect heart rate or diastolic blood pressure; amitriptyline had no effect on any of these cardiovascular measures. These results confirm the antimuscarinic effects of amitriptyline in man, but provide no evidence for antimuscarinic effects of amoxapine. [ABSTRACT FROM AUTHOR]

Speed of onset of antidepressant effect was studied in 20 depressed outpatients assigned double-blind to equipotent doses of amoxapine or amitriptyline. In counterbalanced order, each patient had 2 periods of 3 weeks on active agent interspersed with 2 similar periods of placebo control. On daily and weekly self-ratings, amoxapine was found to reduce symptoms significantly more rapidly than amitriptyline. Psychiatrist-ratings were consonant with selfreports. [ABSTRACT FROM AUTHOR]

The effects of acute and chronic administration of a new antidepressant, amoxapine, on serum prolactin levels were compared to the effects of loxapine, its parent compound, which is a widely used neuroleptic. Serum prolactin levels were significantly elevated after amoxapine. These elevations were not significantly different from those of patients given loxapine. This suggests that amoxapine, in contrast to most other antidepressants, can block dopamine receptors at the anterior pituitary, which usually is associated with blockade of dopamine receptors in the striatum and limbic system, leading to extrapyramidal side effects and antipsychotic properties, respectively. The implications of these findings for the clinical use of amoxapine are discussed, [ABSTRACT FROM AUTHOR]

5-Hydroxytryptamine (5-HT) uptake was studied by using blood platelets from 13 patients with endogenous depression (Hamilton rating scale 33±7) and 13 healthy volunteers. An improved method with a short incubation time and low substrate concentration was used, and the incubation was performed in Krebs-Henscleit buffer (pH 7.4) at 37° C. A clear difference in 5-HT uptake by blood platelets was noted: The V of the reaction in patients was 39, and in controls 71 pmol per 2×10 platelets in 5 min. There was no significant difference in the K. After a 4-week treatment with imipramine, a competitive inhibition of 5-HT uptake with an increased K was seen; after a similar treatment with amoxapine there was little change in 5-HT uptake. Amoxapine was inferior to imipramine as an inhibitor of 5-HT uptake, also in vitro. There was no difference in clinical recovery in these treatment groups. These results may be of importance so as to understand the potential biological differences between depressed patients and normal persons. [ABSTRACT FROM AUTHOR]

This paper reports on an investigation of the effects of the long-term administration of a new dibenzoxapine antidepressant, amoxapine, (200 mg/day), on the nocturnal sleep patterns of a group of normal young males. Continuous polygraphic recordings of sleep were made prior to, during and after discontinuation of the drug. Soporific activity was minimal in these subjects as assessed by sleep latency, wake time and total sleep time. However, sleep architecture was profoundly modified by the drug. Although no notable alterations in stages 1 and 2 were observed, significant increases in stages 3 and 4 (delta) occurred. REM sleep was reduced in a reciprocal manner to delta. These modifications were most pronounced on the initial drug night and, though trending toward the baseline levels during the course of drug administration, persisted throughout the latter. Following discontinuation of the drug, an increase in REM and decrease in delta sleep was noted but the peak intensity of the compensatory trend was delayed until the second week of withdrawal. With respect to its effect on sleep, this new dibenzoxapine compound resembles more closely amitriptyline, a dibenzazapine (tricyclic), than other antidepressants thus far investigated. [ABSTRACT FROM AUTHOR]

A novel protocol for the synthesis of 11-substituted dibenzo[ b, f][1,4]oxazepines is reported. Seven compounds were designed as analogs of the antipsychotic drug loxapine and antidepressant amoxapine. The key transformations include generation of a carbamate intermediate using phenyl chloroformate which avoids the use of harmful phosgene, a microwave-induced transformation of the carbamate intermediate into various urea derivatives, and a subsequent phosphorous oxychloride-induced cyclocondensation. The simple reactions and wide substrate scope enhance the practical application of this methodology. [ABSTRACT FROM AUTHOR]

Non-typhoidal Salmonella ingeniously scavenges energy for growth from tyramine (TYR) and d-glucuronic acid (DGA), both of which occur in the host as the metabolic byproducts of the gut microbial metabolism. A critical first step in energy scavenging from TYR and DGA in Salmonella involves TYR-oxidation via TYR-oxidoreductase and production of free-DGA via β-glucuronidase (GUS)-mediated hydrolysis of d-glucuronides (conjugated form of DGA), respectively. Here, we report that Salmonella utilizes TYR and DGA as sole sources of energy in a serotype-independent manner. Using colorimetric and radiometric approaches, we report that genes SEN2971, SEN3065, and SEN2426 encode TYR-oxidoreductases. Some Salmonella serotypes produce GUS, thus can also scavenge energy from d-glucuronides. We repurposed phenelzine (monoaminoxidase-inhibitor) and amoxapine (GUS-inhibitor) to inhibit the TYR-oxidoreductases and GUS encoded by Salmonella, respectively. We show that phenelzine significantly inhibits the growth of Salmonella by inhibiting TYR-oxidoreductases SEN2971, SEN3065, and SEN2426. Similarly, amoxapine significantly inhibits the growth of Salmonella by inhibiting GUS-mediated hydrolysis of d-glucuronides. Because TYR and DGA serve as potential energy sources for Salmonella growth in vivo, the data and the novel approaches used here provides a better understanding of the role of TYR and DGA in Salmonella pathogenesis and nutritional virulence. [ABSTRACT FROM AUTHOR]

A 37-year-old woman was admitted to our hospital because of acute respiratory distress. Two weeks previously, amoxapine (75 mg/day) had been administered for the first time. Ten days later she developed a high fever, severe hypoxaemia and pulmonary infiltrates on chest CT, including patchy areas of ground-glass opacity, thickening of the interlobular septae and bronchial walls and pleural effusions. BAL showed a predominance of neutrophils, lymphocytes and erythrocytes but not eosinophils. Amoxapine was stopped, resulting in complete resolution of the pulmonary infiltrates. When the patient was re-exposed to amoxapine (52.5 mg total dose), high fever, reduced SaO2 and pulmonary infiltrates reappeared. We concluded that acute respiratory distress may be associated with amoxapine treatment. [ABSTRACT FROM AUTHOR]

This report describes the presentation of neuroleptic malignant syndrome (N0M.S) in the primary care setting in an older adult with major depression with psychosis. This patient had been stable on a regimen of amoxapine, lithium carbonate, lorazepam, and benztropine. The patient had rigidity, altered sensorium, diaphoresis, autonomic instability, elevated WBC count and urine myoglobin, and creatine phosphokinase (CPK) reaching 1331 U/I. He was successfully treated with bromocriptine. [ABSTRACT FROM AUTHOR]

AbstractA 63-year-old man with chronic renal failure who had received hemodialysis three times per week for 4 years developed neuroleptic malignant syndrome 10 days after taking amoxapine. His condition was characterized by muscle rigidity, elevation of body temperature and altered consciousness. Although he was treated with dantrolen and supportive care as well as discontinuation of amoxapine, his condition rapidly deteriorated, resulting in death. Because the pharmacokinetics of drugs, especially those such as antidepressants, in patients with chronic renal failure has not been fully clarified, one should be careful about giving such patients these drugs. [ABSTRACT FROM AUTHOR]

Tricyclic antidepressants are known as potentially inappropriate medications in the elderly. A notification issued in July 2015 in South Korea recommended caution while prescribing tricyclic antidepressants to the elderly. Further, since October 2015, the nationwide computerized drug utilization review monitoring system provides a pop-up window, on a real-time basis, whenever tricyclic antidepressants are prescribed to elderly outpatients. Therefore, we evaluated whether providing drug utilization review information was effective in reducing tricyclic antidepressant prescription to elderly outpatients. We used the Health Insurance Review and Assessment Service-Adult Patient Sample data from 2014 to 2016. Data related to the prescription of tricyclic antidepressants to outpatients aged 65 years or more were extracted. We determined the number of prescriptions per day per 100,000 elderly patients in each month, compared the average number of prescriptions before and after the drug utilization review information was provided, and evaluated the changes in the number of prescriptions by using an interrupted time series analysis. The average number of tricyclic antidepressant prescriptions per day per 100,000 elderly patients decreased from 76.6 (75.5 to 77.6) to 65.7 (64.5 to 66.9), a 14.2% reduction after the provision of drug utilization review information started. Following initiation of provision of drug utilization review information, there was an immediate drop of 9.2 tricyclic antidepressant prescriptions per day per 100,000 elderly patients, whereas there was no statistically significant change in trends. Providing the drug utilization review information on tricyclic antidepressant prescription for the elderly contributed to the reduction in tricyclic antidepressant prescriptions. [ABSTRACT FROM AUTHOR]

ABSTRACT 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 μg three-times daily for 4 weeks). The B12-amoxapine group received the opposite regimen. All patients 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

The article discusses the case of a 67-year-old woman with spinal canal stenosis who developed refractory hypotension during general anaesthesia caused by administering tricyclic antidepressant (TCA), amoxapine. Her medical history included hyperlipidemia, hypertension and depression. After being subjected to anterior fusion of cervical spine, her blood pressure increased as she regained consciousness.

A letter to the editor is presented to report on a case of crossover reaction between a neuroleptic and an antidepressant.

A letter to the editor is presented that reports a case of neuroleptic malignant syndrome which appears to be caused by amoxapine.