Identification of the exosomal PD-L1 inhibitor to promote the PD-1 targeting therapy of gastric cancer.

Programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) targeting therapy is widely applied in clinics for gastric cancer treatment. Nevertheless, the clinical response is not well acceptable due to the exosomal PD-L1. Hence, abrogation of the exosomal PD-L1 may be a strategy to sensitize the gastric cancer cell to PD-1 targeting therapy. With the aid of CD63 targeting antibody and PD-L1 targeting aptamer, HTRF based assay was established to quantify the exosomal PD-L1, and applied to our in-house compound library, resulting in the identification of moclobemide. Further optimization of moclobemide lead to EP16, which can inhibit the generation of exosomal PD-L1 with IC50 = 0.108 µM. By applying EP16 to gastric cancer cell line coupled with T-cell activity related experiment, it was validated to activate T-cell and can promote the response of PD-1 targeting therapy for gastric cancer treatment in vitro and in vivo. Collectively, our findings give a promising tool to promote the sensitivity of anti-PD-1 for gastric cancer treatment, and EP16 can serve as a leading compound for exosomal PD-L1 abrogation.

Serotonin syndrome: A pharmacovigilance comparative study of drugs affecting serotonin levels.

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.

Treatment-Resistant Depression (TRD): Is the Opioid System Involved?

About 30% of major depression disorder patients fail to achieve remission, hence being diagnosed with treatment-resistant major depression (TRD). Opium had been largely used effectively to treat depression for centuries, but when other medications were introduced, its use was discounted due to addiction and other hazards. In a series of previous studies, we evaluated the antinociceptive effects of eight antidepressant medications and their interaction with the opioid system. Mice were tested with a hotplate or tail-flick after being injected with different doses of mianserin, mirtazapine, trazodone, venlafaxine, reboxetine, moclobemide, fluoxetine, or fluvoxamine to determine the effect of each drug in eliciting antinociception. When naloxone inhibited the antinociceptive effect, we further examined the effect of the specific opioid antagonists of each antidepressant drug. Mianserin and mirtazapine (separately) induced dose-dependent antinociception, each one yielding a biphasic dose-response curve, and they were antagonized by naloxone. Trazodone and venlafaxine (separately) induced a dose-dependent antinociceptive effect, antagonized by naloxone. Reboxetine induced a weak antinociceptive effect with no significant opioid involvement, while moclobemide, fluoxetine, and fluvoxamine had no opioid-involved antinociceptive effects. Controlled clinical studies are needed to establish the efficacy of the augmentation of opiate antidepressants in persons with treatment-resistant depression and the optimal dosage of drugs prescribed.

Amidation by reactive extrusion for the synthesis of active pharmaceutical ingredients teriflunomide and moclobemide.

The solventless synthesis of an amide was performed in a twin-screw extruder in the presence of a coupling agent, providing a high yielding and productive method. The reaction conditions were optimized to prepare APIs, teriflunomide and moclobemide.

Anticancer Effects of Antidepressants in Hepatocellular Carcinoma Cells.

BACKGROUND/AIM: An epidemiological investigation indicated that tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) were associated with a lower risk of hepatocellular carcinoma (HCC). Another previous study showed that seven antidepressants inhibited glucocorticoid receptor (GR)-mediated gene transcription, a pathway that is linked to various diseases, including cancer. It is known that the expression levels of GR in cancerous tissues are higher than those in noncancerous tissues in patients with HCC. Notably, among the seven antidepressants, amitriptyline (TCA), desipramine (TCA), and fluoxetine (SSRI) were found to induce apoptosis in HCC cells. Given this, we investigated whether four other GR-specific antidepressants, including mianserin (atypical antidepressant), tianeptine (atypical antidepressant), imipramine (TCA), and moclobemide (monoamine oxidase inhibitor, MAOI) affect the cell viability of HCC. MATERIALS AND METHODS: Cell proliferation and IC50 curves were determined by MTT assays. RESULTS: Imipramine and mianserin significantly inhibited HCC cell viability, whereas moclobemide and tianeptine did not. IC50 showed that the same dose of imipramine or mianserin led to significant inhibitory effects on HCC cells whereas there were only slight effects on normal human hepatocytes (HH). CONCLUSION: According to previous and present findings, TCAs, SSRIs and mianserin may have anti-tumor activity in HCC. However, the appropriate dose, frequency, and route of the administration still need to be determined in future preclinical and clinical studies.

Predicting serotonin toxicity in serotonin reuptake inhibitor overdose.

AIMS: We aimed to investigate the frequency of serotonin toxicity following overdose of antidepressants that inhibit serotonin reuptake and the factors that influence the probability of serotonin toxicity occurring. METHODS: This was a retrospective cohort study of overdoses that included selective serotonin reuptake inhibitors (SSRIs) (70%) and serotonin norepinephrine reuptake inhibitors (SNRIs) (30%) admitted to a tertiary toxicology unit over 23 years. A multivariate mixed effects logistic regression model using NONMEM (7.2.0) was used to determine factors that influenced the probability of serotonin toxicity occurring. RESULTS: There were 1978 overdoses in 1520 patients; median age 33 y (range: 13-86 years) and 64% female. Median defined daily dose equivalent (DDD) was 15 (1-420). Co-ingestants were taken in 1678/1978 (85%) overdoses: 11 co-ingested the monoamine oxidase-A inhibitor (MAOI) moclobemide, 99 (5%) co-ingested olanzapine, 58 (3%) co-ingested risperidone and 417 co-ingested a benzodiazepine (21%). Serotonin toxicity occurred in 269 overdoses (13.6%). The probability of serotonin toxicity increased slightly per 10 DDD units dose [OR, 1.01; 95% confidence intervals (CIs): 0.93-1.10], increased for an SNRI vs. an SSRI [OR, 1.07; 95% CI: 0.99-1.15], and markedly increased with co-ingestion of moclobemide [OR, 33.12; 95% CI: 7.5-147]. The probability decreased per 10 y age [OR, 0.84; 95% CI: 0.74-0.95], and with co-ingestion of the serotonin 2 A receptor (5-HT2A) antagonists olanzapine [OR, 0.40; 95% CI: 0.17-0.94] or risperidone [OR, 0.13; 95% CI: 0.02-0.99]. The probability of serotonin toxicity was 12.5% at 1 DDD (therapeutic), 12.7% at 15 DDDs and 19% at 420 DDDs. In overdoses of the median dose of 15 DDDs, co-ingestion of moclobemide increased the probability to 83%, and co-ingestion of olanzapine or risperidone decreased it to 5.5% and 1.8%, respectively. CONCLUSIONS: Serotonin toxicity is common following SSRI/SNRI overdose. Although dose increases probability, this was only a small effect. Co-ingestion with olanzapine or risperidone reduced the risk 2-6-fold, and moclobemide increased the risk 5-fold.

ARIMA model in predicting of COVID-19 epidemic for the Southern Africa region

Background: Coronavirus pandemic, a serious global public health threat, affects the Southern African countries more than any other country on the continent. The region has become the epicenter of the coronavirus with South Africa accounting for the most cases. To cap the deadly effect caused by the pandemic, we apply a statistical modelling approach to investigate and predict COVID-19 incidence. Methods: Using secondary data on the daily confirmed COVID-19 cases per million for Southern Africa Development Community (SADC) member states from March 5, 2020, to July 15, 2021, we model and forecast the spread of coronavirus in the region. We select the best ARIMA model based on the log-likelihood, AIC, and BIC of the fitted models. Results: The ARIMA (11,1,11) model for the complete data set was finally selected among ARIMA models based upon the parameter test and the Box­Ljung test. The ARIMA (11,1,9) was the best candidate for the training set. A 15-day forecast was also made from the model, which shows a perfect fit with the testing set. Conclusion: The number of new COVID-19 cases per million for the SADC shows a downward trend, but the trend is characterized by peaks from time to time. Tightening up of the preventive measures continuously needs to be adapted in order to eradicate the coronavirus epidemic from the population.

Design, synthesis, and computational studies of phenylacetamides as antidepressant agents.

In the present work, a hit molecule obtained from zinc 'clean drug-like database' by systematically performed computational studies was modified chemically to obtain different derivatives (VS1-VS25). Structures of synthesized derivatives were confirmed by IR, 1H-NMR, 13C-NMR, 13C-DEPT, MS, and elemental analysis. All the synthesized compounds were biologically evaluated for their antidepressant activity by using tail suspension test and forced swimming test in albino mice. All these derivatives showed moderate to good antidepressant activity. The most potent compound (VS25) among the synthesized compounds showed better antidepressant potential than the standard drugs moclobemide, imipramine, and fluoxetine. To understand the time-dependent interactions of this most active compound with MAO-A molecular dynamics was carried out and reported here. Additionally, acute oral toxicity was performed for the most active compound as per OECD guidelines.

Monoamine oxidase inhibitors (MAOI): pharmacology, metabolism and application in the treatment of depression / Inhibitory monoaminooksydazy (IMAO): farmakologia, metabolizm i zastosowanie w terapii depresji o róznej etiologii.

The aim of this article is to synthesize informations about monoamine oxidase inhibitors drugs (MAOI) used in the treatment of depression. General informations on monoamine oxidase (MAO) and its kinetic properties are presented. MAO is an enzyme that degrades catecholamines and their 3-methoxy derivatives and other monoamines, for example serotonin or tryptamine. The criteria and symptoms of depressive disorders are discussed. They have to be distinguished from the state of sadness and similar states. The basic symptoms include: voice, facial expressions, anhedonia and psychomotor slowness. They may differ in individual diagnostic units. The following basic mechanism of the pharmacological action of MAOI has been indicated: when a drug inhibits MAO, the degradation of monoamines decreases and the concentration of the neurotransmitter in the synaptic cleft increases. Informations on selected selective and reversible MAOI-A are presented in the following sections. These are currently the safest and most effective MAOI drugs that can be used in the treatment of depressive diseases. The following drugs are discussed: moclobemide, befloxatone, toloxatone and brofaromine. Final conclusions are given and the presented data summarized.

Antidepressant-like effect of dehydrozingerone from Zingiber officinale by elevating monoamines in brain: in silico and in vivo studies.

BACKGROUND: Dehydrozingerone (DHZ) is an active ingredient of Zingiber officinale and structural half analogue of curcumin. In the present study, DHZ was evaluated for monoamine oxidase (MAO) inhibitory activity in silico and antidepressant activity in vivo. METHOD: The binding affinity of DHZ with MAO-A (PDB ID: 2Z5Y) was assessed using Schrodinger's Maestro followed by free energy calculation, pharmacokinetic property prediction using Qikprop and Molecular dynamics simulation using Desmond. In vivo antidepressant activity of DHZ was evaluated on C57 BL/6 male mice using Escilatopram as the standard antidepressant. Open field test (OFT), forced swimming test (FST) and tail suspension test (TST) were used to evaluate the antidepressant effect of the drugs on days 1 and 7. Following the behavioural study, neurotransmitters (noradrenaline, dopamine and serotonin) were estimated using liquid chromatography-mass spectrometry. RESULTS: DHZ demonstrated a greater binding affinity for the MAO-A enzyme compared to moclobemide in silico. Immobility in TST and FST were significantly (p < 0.05) reduced in vivo with 100mg/kg DHZ as compared to respective controls. DHZ treatment was more effective 1 h post treatment compared to vehicle control. A significant increase in levels of neurotransmitters was observed in mice brain homogenate in response to DHZ treatment, reassuring its antidepressant-like potential. CONCLUSION: DHZ demonstrated MAO-A inhibition in silico, and the increased neurotransmitter levels in the brain in vivo were associated with an antidepressant-like effect.

Acute and chronic treatment with moclobemide, a reversible MAO-inhibitor, potentiates the antielectroshock activity of conventional antiepileptic drugs in mice.

BACKGROUND: Due to enhancing serotonergic and noradrenergic neurotransmission, moclobemide may influence seizure phenomena. In this study, we examined the effect of both acute and chronic treatment with moclobemide on seizures and the action of first-generation antiepileptic drugs: valproate, carbamazepine, phenobarbital and phenytoin. METHODS: The effect of moclobemide on seizures was assessed in the electroconvulsive threshold test, while its influence on antiepileptic drugs was estimated in the maximal electroshock test in mice. Undesired effects were evaluated in the chimney test (motor impairment) and step-through passive-avoidance task (long-term memory deficits). Finally, brain concentrations of antiepileptics were determined by fluorescence polarization immunoassay. RESULTS: Given acutely, moclobemide at 62.5 and 75 mg/kg increased the electroconvulsive threshold. In contrast, chronic treatment with moclobemide up to 75 mg/kg did not influence this parameter. Acute moclobemide applied at subthreshold doses (up to 50 mg/kg) enhanced the antielectroshock effects of carbamazepine, valproate and phenobarbital. Chronic moclobemide (37.5-75 mg/kg) increased the action of all four antiepileptic drugs. All revealed interactions, except these between moclobemide and phenobarbital, seem to have pharmacokinetic nature, because the antidepressant drug, either in acute or in chronic treatment, increased the brain concentrations of respective antiepileptic drugs. In terms of undesired neurotoxic effects, acute and chronic moclobemide, antiepileptic drugs, and their combinations did not produce significant motor or long-term memory impairment. CONCLUSIONS: Acute and chronic therapy with moclobemide can increase the effectiveness of some antiepileptic drugs against the maximal electroshock test. In mice, this effect was, at least partially, due to pharmacokinetic interactions. So far as the results of experimental studies can be transferred to clinical conditions, moclobemide seems safe for the application in patients with epilepsy and depression. Possibly, in the case of certain antiepileptic drugs combined with moclobemide, their doses should be adjusted downwards.

Monoamine oxidase A inhibition with moclobemide enhances the anti-parkinsonian effect of L-DOPA in the MPTP-lesioned marmoset.

Whereas monoamine oxidase (MAO) type B inhibitors are used as adjunct to L-3,4-dihydroxyphenylalanine (L-DOPA) in the treatment of Parkinson's disease (PD), the enzyme MAO type A (MAO-A) also participates in the metabolism of dopamine in the human and primate striatum. Here, we sought to assess the effect of the selective reversible MAO-A inhibitor moclobemide on L-DOPA anti-parkinsonian in the gold standard animal model of PD, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. We also assessed the effect of moclobemide on L-DOPA-induced dyskinesia and psychosis-like behaviours (PLBs). Experiments were performed in six MPTP-lesioned marmosets chronically treated with L-DOPA and exhibiting stable dyskinesia and PLBs upon each administration. In a randomised within-subject design, animals were administered a therapeutic dose of L-DOPA in combination with moclobemide (0.1, 1 and 10 mg/kg) or its vehicle, after which the severity of parkinsonism, dyskinesia, and PLBs was rated by an experienced blinded rater. Moclobemide significantly reduced the global parkinsonian disability (- 36% with 0.1 mg/kg, P < 0.05; - 38% with 1 mg/kg, P < 0.01; - 47% with 10 mg/kg, P < 0.01), when compared with its vehicle. This reduction of parkinsonism was not accompanied by an exacerbation of dyskinesia or PLBs. Reversible MAO-A inhibition with moclobemide appears as an effective way to increase the anti-parkinsonian action of L-DOPA, without negatively affecting dyskinesia or dopaminergic psychosis.

Monoamine oxidase A inhibition as monotherapy reverses parkinsonism in the MPTP-lesioned marmoset.

Monoamine oxidase (MAO) type B (MAO-B) inhibition was shown to confer anti-parkinsonian benefit as monotherapy and adjunct to L-3,4-dihydroxyphenylalanine (L-DOPA) in clinical trials. Here, we explore the anti-parkinsonian effect of MAO type A (MAO-A) inhibition as monotherapy, as the enzyme MAO-A is also encountered within the primate and human basal ganglia, where it metabolises dopamine, albeit to a lesser extent than MAO-B. In six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets, we assessed the anti-parkinsonian effect of the reversible MAO-A inhibitor moclobemide (0.1 and 1 mg/kg) as monotherapy and compared it to that of L-DOPA and vehicle treatments. Moclobemide significantly reversed parkinsonism (by 39%, P < 0.01), while eliciting only mild dyskinesia and psychosis-like behaviours (PLBs). In contrast, L-DOPA anti-parkinsonian effect was accompanied by marked dyskinesia and PLBs. MAO-A inhibition with moclobemide may provide anti-parkinsonian benefit when administered without L-DOPA and might perhaps be considered as monotherapy for the treatment of Parkinson's disease in the early stages of the condition.

Effect of antidepressants for cessation therapy in betel-quid use disorder: a randomised, double-blind, placebo-controlled trial.

AIMS: More than one-half of betel-quid (BQ) chewers have betel-quid use disorder (BUD). However, no medication has been approved. We performed a randomised clinical trial to test the efficacy of taking escitalopram and moclobemide antidepressants on betel-quid chewing cessation (BQ-CC) treatment. METHODS: We enrolled 111 eligible male BUD patients. They were double-blinded, placebo-controlled and randomised into three treatment groups: escitalopram 10 mg/tab daily, moclobemide 150 mg/tab daily and placebo. Patients were followed-up every 2 weeks and the length of the trial was 8 weeks. The primary outcome was BQ-CC, defined as BUD patients who continuously stopped BQ use for ⩾6 weeks. The secondary outcomes were the frequency and amount of BQ intake, and two psychological rating scales. Several clinical adverse effects were measured during the 8-week treatment. RESULTS: Intention-to-treat analysis shows that after 8 weeks, two (5.4%), 13 (34.2%) and 12 (33.3%) of BUD patients continuously quit BQ chewing for ⩾6 weeks among placebo, escitalopram, moclobemide groups, respectively. The adjusted proportion ratio of BQ-CC was 6.3 (95% CI 1.5-26.1) and 6.8 (95% CI 1.6-28.0) for BUD patients who used escitalopram and moclobemide, respectively, as compared with those who used placebo. BUD patients with escitalopram and moclobemide treatments both exhibited a significantly lower frequency and amount of BQ intake at the 8th week than those with placebo. CONCLUSIONS: Prescribing a fixed dose of moclobemide and escitalopram to BUD patients over 8 weeks demonstrated treatment benefits to BQ-CC. Given a relatively small sample, this study provides preliminary evidence and requires replication in larger trials.

Influence of the endocannabinoid system on the antidepressant activity of bupropion and moclobemide in the behavioural tests in mice.

BACKGROUND: Though there are several classes of antidepressant drugs available on the pharmaceutical market, depression that affects globally over 320 million people is still undertreated. Scientists have made attempts to develop novel therapeutical strategies to maximize effectiveness of therapy and minimize undesired reactions. One of the ideas is use of either dual-action agents or combined administration of two substances that affect diverse neurotransmissions. Thus, we investigated whether the selected CB receptor ligands (oleamide, AM251, JWH133, and AM630) can have an impact on the activity of bupropion and moclobemide. Bupropion belongs to the dual acting drugs, whereas moclobemide is an inhibitor of monoamine oxidase. METHODS: The mice forced swim test and the tail suspension test were applied in order to determine the potential antidepressant-like activity, whereas the HPLC method was used in order to assess the brain concentrations of the tested antidepressants. RESULTS: An intraperitoneal injection of sub-effective doses of oleamide (5 mg/kg), AM251 (0.25 mg/kg), and AM630 (0.25 mg/kg) increased activity of bupropion (10 mg/kg) in both behavioural tests. Effects of moclobemide (1.5 mg/kg) were potentiated only by AM251. These results were not influenced by the hypo- or hyperlocomotion of animals. CONCLUSION: The outcomes of the present study revealed that particularly activation or inhibition of the CB1 receptor function may augment the antidepressant activity of bupropion, whereas only inhibition of the CB1 receptor function manages to increase activity of moclobemide. Most probably, an interplay between CB receptor ligands and bupropion or moclobemide takes place at the cellular level.

Administration of moclobemide facilitates fear extinction and attenuates anxiety-like behaviors by regulating synaptic-associated proteins in a rat model of post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a long-lasting mental disorder and accompanied by worse fear extinction. Enhanced fear memory or poor fear extinction are typical features of PTSD. Dysfunction of the serotonergic neurotransmitter system is involved in numerous mental and behavioral disorders. Monoamine oxidase A (MAOA) is important in the metabolism of serotonin and play an important role in behavious. The aim of this study was to explore the change of MAOA and effect of MAOA on fear memory in PTSD. We used single prolonged stress (SPS) to create animal model of PTSD. A startle/fear box and elevated plus maze were used to observe fear memory and anxiety level, respectively. We examined the expression of MAOA and synaptic marker protein, as well as the immunological activity of MAOA in the infralimbic cortex (IL) area, which is a critical brain region involved in emotions, especially fear regulation. We found increased anxiety-like behavior, dysfunction in fear extinction, and increased MAOA in SPS rats. After treatment with moclobemide (a selective inhibitor of MAOA), SPS rats showed significantly improved fear memory and decreased anxiety-like behavior, which indicated that moclobemide could reverse fear extinction deficit and attenuate abnormally increased levels of anxiety caused by SPS in short term. On the contrary, decreased PSD-95 and SYN1 expression in the IL region were also reversed by moclobemide. These results suggest that increased MAOA play a negative role in fear extinction and levels of anxiety in PTSD, which may be involved in change in PSD-95 and SYN1.

Bioavailability of moclobemide from two formulation tablets in healthy humans.

A ,,sine qua non" requirement for a generic formulation to be admitted for a medical use is to provide bioavailability studies in healthy subjects. Therefore, those studies were performed for 150 mg moclobemide tablets (Jelfa, Poland) versus 150 mg Aurorix (Hoffmann la Roche) reference tablets. An open-label, two-phase crossover study was conducted with 10 healthy subjects. Pharmacokinetic parameters (AUC, ke, t1/2, Cmax, tmax, tlag, V/f, Cl/f) obtained at the same time for moclobemide were supposed to be confronted with the literature data available for healthy volunteers. The plasma moclobemide levels as a function of time were calculated according to either an open one-compartment body model with lag time of absorption or non-compartmental method for calculation of bioavailability using Phoenix WinNonlin 8.0 software. For those reasons a suitable HPLC method was worked out. Carbamazepine was proposed as an internal standard and ammonia as well as Na2HPO4 as alkalizing agents for the mobile phase and the liquid-liquid extraction of moclobemide from human blood plasma, respectively. Basic pharmacokinetic parameters of moclobemide obtained in the paper are essentially equal to the literature data for the healthy subjects. However, bioavailability parameters (AUC0→t, AUC0→∞, Cmax, tmax) were greater for moclobemide tablets (Jelfa) if compared to Aurorix tablets (Roche) by more than 20 %. Furthermore, the extent of bioavailability (110.6 %) for the generic moclobemide tablets if compared to Aurorix tablets is not significantly different. It seems to us that the number of subjects should be increased from 10 to 24 to help to clarify that inconsequence.