Search

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]

Alzheimer's disease (AD) is accompanied by behavioral and psychological symptoms of dementia (BPSD), which is often alleviated by treatment with psychotropic drugs, such as antidepressants, hypnotics, and anxiolytics. If these drugs also inhibit acetylcholinesterase (AChE) activity, they may contribute to the suppression of AD progression by increasing brain acetylcholine concentrations. We tested the potential inhibitory effects of 31 antidepressants, 21 hypnotics, and 12 anxiolytics on recombinant human AChE (rhAChE) activity. At a concentration of 10 -4  M, 22 antidepressants, 19 hypnotics, and 11 anxiolytics inhibited rhAChE activity by <20%, whereas nine antidepressants (clomipramine, amoxapine, setiptiline, nefazodone, paroxetine, sertraline, citalopram, escitalopram, and mirtazapine), two hypnotics (triazolam and brotizolam), and one anxiolytic (buspirone) inhibited rhAChE activity by ≥20%. Brotizolam (≥10 -6 M) exhibited stronger inhibition of rhAChE activity than the other drugs, with its pIC 50 value being 4.57 ± 0.02. The pIC 50 values of the other drugs were <4, and they showed inhibitory activities toward rhAChE at the following concentrations: ≥3 × 10 -6  M (sertraline and buspirone), ≥10 -5  M (amoxapine, nefazodone, paroxetine, citalopram, escitalopram, mirtazapine, and triazolam), and ≥3 × 10 -5  M (clomipramine and setiptiline). Among these drugs, only nefazodone inhibited rhAChE activity within the blood concentration range achievable at clinical doses. Therefore, nefazodone may not only improve the depressive symptoms of BPSD through its antidepressant actions but also slow the progression of cognitive symptoms of AD through its AChE inhibitory actions.

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]

The tricyclic antidepressant amoxapine (AMX) has been reported for a rapid onset of action compared to other cyclic antidepressants. It has very low solubility and bioavailability due to first-pass metabolism. Therefore, we planned to develop solid lipid nanoparticles (SLNs) of AMX using a single emulsification method to increase its solubility and bioavailability. HPLC and LC-MS/MS methods were developed further to quantify AMX in the formulation, plasma, and brain tissue samples. The formulation was studied for entrapment efficiency, loading, and in vitro drug release. Particle size and ζ potential analyses, AFM, SEM, TEM, DSC, and XRD were used for further characterization. In vivo oral pharmacokinetic and brain pharmacokinetic studies were performed using Wistar rats. The entrapment and loading efficiencies of AMX in SLNs were 85.8 ± 3.42 and 4.5 ± 0.45%, respectively. The developed formulation had a mean particle size of 151.5 ± 7.02 nm and a polydispersity index of 0.40 ± 0.11. DSC and XRD results indicated that AMX was incorporated into the nanocarrier system in an amorphous form. SEM, TEM, and AFM studies of AMX-SLNs confirmed the particles' spherical shape and nanoscale size. AMX solubility increased by approx. 2.67 times compared to the pure drug. The developed LC-MS/MS method was successfully applied to the oral and brain pharmacokinetic study of AMX-loaded SLNs in rats. Oral bioavailability was enhanced 1.6 times compared to the pure drug. The peak plasma concentrations of pure AMX and AMX-SLNs were 617.4 ± 137.4 and 1043.5 ± 150.2 (ng/mL), respectively. AMX-SLNs showed more than 5.8 times brain concentration compared to the pure drug. Based on the findings, it appears that utilizing a solid lipid nanoparticle carrier to transport AMX can be a highly effective delivery method with improved pharmacokinetic properties in the brain. This approach may prove valuable for future antidepressant treatment.

Aim: Amoxapine (AMX) has been reported to be metabolized by CYP3A4 and CYP2D6. Naringin (NG) has been reported to inhibit CYP enzymes. Therefore, the current work was designed to develop AMX solid lipid nanoparticles (AMX-SLNs) and NG-SLNs for better therapeutic performance. Materials & methods: AMX-SLNs and NG-SLNs were prepared and characterized. AMX and NG interactions with CYP450s were studied with molecular docking to rationalize the effectiveness of the combination. Results: AMX-SLNs and NG-SLNs showed nanometric size with a sustained in vitro drug-release profile. NG showed a higher predicted binding affinity for CYP3A4 and CYP2D6, suggesting the potential for inhibition. Conclusion: The developed formulations were thoroughly characterized along with molecular docking data indicating promising AMX and NG combinations that may show good therapeutic activity.