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Neurotherapeutics : the Journal of the... Jul 2021The continuous adherence to the conventional "one target, one drug" paradigm has failed so far to provide effective therapeutic solutions for heterogeneous and...
The continuous adherence to the conventional "one target, one drug" paradigm has failed so far to provide effective therapeutic solutions for heterogeneous and multifactorial diseases as amyotrophic lateral sclerosis (ALS), a rare progressive and chronic, debilitating neurological disease for which no cure is available. The present study is aimed at finding innovative solutions and paradigms for therapy in ALS pathogenesis, by exploiting new insights from Network Medicine and drug repurposing strategies. To identify new drug-ALS disease associations, we exploited SAveRUNNER, a recently developed network-based algorithm for drug repurposing, which quantifies the proximity of disease-associated genes to drug targets in the human interactome. We prioritized 403 SAveRUNNER-predicted drugs according to decreasing values of network similarity with ALS. Among catecholamine, dopamine, serotonin, histamine, and GABA receptor modulators, as well as angiotensin-converting enzymes, cyclooxygenase isozymes, and serotonin transporter inhibitors, we found some interesting no customary ALS drugs, including amoxapine, clomipramine, mianserin, and modafinil. Furthermore, we strengthened the SAveRUNNER predictions by a gene set enrichment analysis that confirmed modafinil as a drug with the highest score among the 121 identified drugs with a score > 0. Our results contribute to gathering further proofs of innovative solutions for therapy in ALS pathogenesis.
Topics: Algorithms; Amyotrophic Lateral Sclerosis; Central Nervous System Stimulants; Drug Repositioning; Gene Regulatory Networks; Humans; Protein Interaction Domains and Motifs; Protein Kinase Inhibitors
PubMed: 33987813
DOI: 10.1007/s13311-021-01064-z -
Pathogens (Basel, Switzerland) Apr 2021Non-typhoidal 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...
Non-typhoidal 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 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 utilizes TYR and DGA as sole sources of energy in a serotype-independent manner. Using colorimetric and radiometric approaches, we report that genes , , and encode TYR-oxidoreductases. Some 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 , respectively. We show that phenelzine significantly inhibits the growth of by inhibiting TYR-oxidoreductases SEN2971, SEN3065, and SEN2426. Similarly, amoxapine significantly inhibits the growth of by inhibiting GUS-mediated hydrolysis of d-glucuronides. Because TYR and DGA serve as potential energy sources for growth in vivo, the data and the novel approaches used here provides a better understanding of the role of TYR and DGA in pathogenesis and nutritional virulence.
PubMed: 33924374
DOI: 10.3390/pathogens10040469 -
Cells Mar 2021Antidepressants are well-known drugs to treat depression and major depressive disorder for humans. However, the misuse and abuse of antidepressants keep increasing with...
Antidepressants are well-known drugs to treat depression and major depressive disorder for humans. However, the misuse and abuse of antidepressants keep increasing with several side effects reported. The aim of this study was to assess the potential adverse effects of 18 antidepressants by monitoring zebrafish larval locomotor activity performance based on the total distance traveled, burst movement count, and total rotation count at four dark-light intercalated phases. In general, zebrafish larvae displayed sedative effects after antidepressant exposure by showing a significant reduction in all of the locomotor activity-related endpoints. However, three antidepressants i.e., amitriptyline, amoxapine, and sertraline were able to trigger a significantly high locomotor activity in zebrafish larvae during the light cycle. These differences might be due to the pharmacologic differences among the antidepressants. In addition, since each antidepressant possesses a different dosage range from the other, overdoses of these antidepressants might also be the causes of these differences. Furthermore, based on these results, a further study was conducted to observe the effect of these three antidepressants in lower concentrations. From the results, biphasic effects in terms of zebrafish larval locomotor activity were demonstrated by these drugs. Even though further studies are still required to validate the mechanism, these findings indicate that these antidepressants might share a common mechanism responsible for their effects on zebrafish larval locomotor activity although there were some differences in potency of these effects.
Topics: Amitriptyline; Amoxapine; Animals; Antidepressive Agents; Biological Assay; Drug Evaluation, Preclinical; Larva; Locomotion; Phenomics; Principal Component Analysis; Sertraline; Zebrafish
PubMed: 33810553
DOI: 10.3390/cells10040738 -
Dalton Transactions (Cambridge, England... Jan 2021The piperazine scaffold is a privileged structure frequently found in biologically active compounds. Piperazine nucleus is found in many marketed drugs in the realm of... (Review)
Review
The piperazine scaffold is a privileged structure frequently found in biologically active compounds. Piperazine nucleus is found in many marketed drugs in the realm of antidepressants (amoxapine), antipsychotics (bifeprunox), antihistamines (cyclizine and oxatomide), antifungals (itraconazole), antibiotics (ciprofloxacin), etc. This is one of the reasons why piperazine based compounds are gaining prominence in today's research. In addition to the ring carbons, substitution in the nitrogen atom of piperazine not only creates potential drug molecules but also makes it unique with versatile binding possibilities with metal ions. Piperazine ring-based compounds find their application in biological systems with antihistamine, anticancer, antimicrobial and antioxidant properties. They have also been successfully used in the field of catalysis and metal organic frameworks (MOFs). The present review focuses on the synthesis and application of different piperazine derivatives and their metal complexes having diverse applications.
Topics: Chemistry Techniques, Synthetic; Coordination Complexes; Ligands; Piperazine
PubMed: 33416816
DOI: 10.1039/d0dt03569f -
Expert Review of Clinical Pharmacology Dec 2020: Comorbidities of epilepsy may significantly interfere with its treatment as diseases in the general population are also encountered in epilepsy patients and some of... (Review)
Review
: Comorbidities of epilepsy may significantly interfere with its treatment as diseases in the general population are also encountered in epilepsy patients and some of them even more frequently (for instance, depression, anxiety, or heart disease). Obviously, some drugs approved for other than epilepsy indications can modify the anticonvulsant activity of antiepileptics. : This review highlights the drug-drug interactions between antiepileptics and aminophylline, some antidepressant, antiarrhythmic (class I-IV), selected antihypertensive drugs and non-barbiturate injectable anesthetics (ketamine, propofol, etomidate, and alphaxalone). The data were reviewed mainly from experimental models of seizures. Whenever possible, clinical data were provided. PUBMED data base was the main search source.: Aminophylline generally reduced the protective activity of antiepileptics, which, to a certain degree, was consistent with scarce clinical data on methylxanthine derivatives and worse seizure control. The only antiarrhythmic with this profile of action was mexiletine when co-administered with VPA. Among antidepressants and non-barbiturate injectable anesthetics, trazodone, mianserin and etomidate or alphaxalone, respectively, negatively affected the anticonvulsant action of some antiepileptic drugs. Clinical data indicate that only amoxapine, bupropion, clomipramine and maprotiline should be used with caution. Possibly, drugs reducing the anticonvulsant potential of antiepileptics should be avoided in epilepsy patients.
Topics: Animals; Anticonvulsants; Comorbidity; Drug Interactions; Epilepsy; Humans; Seizures
PubMed: 33305639
DOI: 10.1080/17512433.2020.1850258 -
Hinyokika Kiyo. Acta Urologica Japonica Oct 2020A 27-year-old man was referred to our hospital with right-sided back pain and renal dysfunction. Computed tomography revealed a right-sided horseshoe kidney with...
A 27-year-old man was referred to our hospital with right-sided back pain and renal dysfunction. Computed tomography revealed a right-sided horseshoe kidney with hydronephrosis and a thin renal cortex. Diuretic renography revealed a nonfunctioning right kidney. We diagnosed the patient with a symptomatic nonfunctioning right kidney and performed laparoscopic right heminephrectomy. His right-sided back pain reduced postoperatively ; however, he developed retrograde ejaculation, which was attributable to intraoperative injury to the superior hypogastric nerve plexus. We treated the patient with amoxapine (an antidepressant), which led to improvement in retrograde ejaculation.
Topics: Adult; Ejaculation; Fused Kidney; Humans; Kidney; Laparoscopy; Male; Nephrectomy
PubMed: 33271647
DOI: 10.14989/ActaUrolJap_66_10_343 -
Frontiers in Genetics 2020Genetic and environmental factors, alone or in combination, contribute to the pathogenesis of autism spectrum disorder (ASD). Although many protein-coding genes have now...
Genetic and environmental factors, alone or in combination, contribute to the pathogenesis of autism spectrum disorder (ASD). Although many protein-coding genes have now been identified as disease risk genes for ASD, a detailed illustration of long non-coding RNAs (lncRNAs) associated with ASD remains elusive. In this study, we first identified ASD-related lncRNAs based on genomic variant data of individuals with ASD from a twin study. In total, 532 ASD-related lncRNAs were identified, and 86.7% of these ASD-related lncRNAs were further validated by an independent copy number variant (CNV) dataset. Then, the functions and associated biological pathways of ASD-related lncRNAs were explored by enrichment analysis of their three different types of functional neighbor genes (i.e., genomic neighbors, competing endogenous RNA (ceRNA) neighbors, and gene co-expression neighbors in the cortex). The results have shown that most of the functional neighbor genes of ASD-related lncRNAs were enriched in nervous system development, inflammatory responses, and transcriptional regulation. Moreover, we explored the differential functions of ASD-related lncRNAs in distinct brain regions by using gene co-expression network analysis based on tissue-specific gene expression profiles. As a set, ASD-related lncRNAs were mainly associated with nervous system development and dopaminergic synapse in the cortex, but associated with transcriptional regulation in the cerebellum. In addition, a functional network analysis was conducted for the highly reliable functional neighbor genes of ASD-related lncRNAs. We found that all the highly reliable functional neighbor genes were connected in a single functional network, which provided additional clues for the action mechanisms of ASD-related lncRNAs. Finally, we predicted several potential drugs based on the enrichment of drug-induced pathway sets in the ASD-altered biological pathway list. Among these drugs, several (e.g., amoxapine, piperine, and diflunisal) were partly supported by the previous reports. In conclusion, ASD-related lncRNAs participated in the pathogenesis of ASD through various known biological pathways, which may be differential in distinct brain regions. Detailed investigation into ASD-related lncRNAs can provide clues for developing potential ASD diagnosis biomarkers and therapy.
PubMed: 33193567
DOI: 10.3389/fgene.2020.00849 -
Chemical & Pharmaceutical Bulletin 2020The degradation behavior of eight tricyclic antidepressants (TCAs; amitriptyline, amoxapine (AMX), imipramine, clomipramine, desipramine, doxepin, dothiepin, and...
The degradation behavior of eight tricyclic antidepressants (TCAs; amitriptyline, amoxapine (AMX), imipramine, clomipramine, desipramine, doxepin, dothiepin, and nortriptyline) in artificial gastric juice was investigated to estimate their pharmacokinetics in the stomach. As a result, among the eight TCAs, only AMX was degraded in artificial gastric juice. The degradation was a pseudo first-order reaction; activation energy (Ea) was 88.70 kJ/mol and activation entropy (ΔS) was -80.73 J/K·mol. On the other hand, the recovery experiment revealed that the degradation product did not revert to AMX and accordingly, this reaction was considered to be irreversible. In the AMX degradation experiment, peaks considered to be degradation products A (I) and B (II) were detected at retention times of around 3 min and 30 min in LC/UV measurements, respectively. Structural analysis revealed that compound (I) was [2-(2-aminophenoxy)-5-chlorophenyl]-piperazin-1-yl-methanone, a new compound, and compound (II) was 2-chlorodibenzo[b,f][1,4]oxazepin-11(10H)-one. As for the degradation behavior, it was estimated that AMX was degraded into (II) via (I), i.e., (II) was the final product. The results are expected to be useful in clinical chemistry and forensic science, including the estimation of drugs to be used at the time of judicial dissection and suspected drug addiction.
Topics: Amoxapine; Antidepressive Agents, Tricyclic; Chromatography, Liquid; Gastric Juice; Humans; Mass Spectrometry; Molecular Structure
PubMed: 32879225
DOI: 10.1248/cpb.c20-00313 -
Toxicological Sciences : An Official... Nov 2020Seizures are life-threatening adverse drug reactions which are investigated late in drug development using rodent models. Consequently, if seizures are detected, a lot...
Seizures are life-threatening adverse drug reactions which are investigated late in drug development using rodent models. Consequently, if seizures are detected, a lot of time, money and animals have been used. Thus, there is a need for in vitro screening models using human cells to circumvent interspecies translation. We assessed the suitability of cocultures of human-induced pluripotent stem cell (hiPSC)-derived neurons and astrocytes compared with rodent primary cortical cultures for in vitro seizure liability assessment using microelectrode arrays. hiPSC-derived and rodent primary cortical neuronal cocultures were exposed to 9 known (non)seizurogenic compounds (pentylenetetrazole, amoxapine, enoxacin, amoxicillin, linopirdine, pilocarpine, chlorpromazine, phenytoin, and acetaminophen) to assess effects on neuronal network activity using microelectrode array recordings. All compounds affect activity in hiPSC-derived cocultures. In rodent primary cultures all compounds, except amoxicillin changed activity. Changes in activity patterns for both cell models differ for different classes of compounds. Both models had a comparable sensitivity for exposure to amoxapine (lowest observed effect concentration [LOEC] 0.03 µM), linopirdine (LOEC 1 µM), and pilocarpine (LOEC 0.3 µM). However, hiPSC-derived cultures were about 3 times more sensitive for exposure to pentylenetetrazole (LOEC 30 µM) than rodent primary cortical cultures (LOEC 100 µM). Sensitivity of hiPSC-derived cultures for chlorpromazine, phenytoin, and enoxacin was 10-30 times higher (LOECs 0.1, 0.3, and 0.1 µM, respectively) than in rodent cultures (LOECs 10, 3, and 3 µM, respectively). Our data indicate that hiPSC-derived neuronal cocultures may outperform rodent primary cortical cultures with respect to detecting seizures, thereby paving the way towards animal-free seizure assessment.
Topics: Animals; Cells, Cultured; Coculture Techniques; Humans; Induced Pluripotent Stem Cells; Neurons; Rodentia; Seizures
PubMed: 32866265
DOI: 10.1093/toxsci/kfaa136 -
Neuroscience Research Sep 2021Two-pore domain K channels (K2Ps) regulate the resting membrane potential in excitable cells and determine ease of depolarization. Gain-of-function (gf) mutations in one...
Two-pore domain K channels (K2Ps) regulate the resting membrane potential in excitable cells and determine ease of depolarization. Gain-of-function (gf) mutations in one of these channels (unc-58) in C. elegans switch it to a Na conductance channel and cause tremors, paralysis and other defects. We hypothesized that it should be possible to identify drugs that corrected these defects in unc-58(gf) mutant animals by blocking or modulating the over-active channels. We examined dispersal of animals on food because the absence of effective forward locomotion is the most obvious defect. In addition, we quantified egg release over 24 h. Starting with a known inhibitor of mammalian K2Ps and directed structure-based screening, we evaluated numerous drugs in these assays. Loratadine, which inhibits human KCNK18, significantly improved movement as did methiothepin. We confirmed that endosulfan, a GABA-A receptor antagonist, corrected locomotion in the unc-58(gf) strains. Based on structural similarities to other hits, we found that clozapine, loxapine and amoxapine potently suppressed abnormal phenotypes. Curiously, nimodipine, a Ca-channel blocker, dramatically improved movement and egg laying in unc-58(e665), but not unc-58(n495) animals. Molecular modeling provided initial insights into a possible basis for this difference based on the location of the e665 and n495 mutations. This research may lead to identification of novel K2P modulators and potential leads for drug discovery.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Clozapine; Endosulfan; Gain of Function Mutation; Humans; Mutation; Nimodipine; Potassium Channels
PubMed: 32681854
DOI: 10.1016/j.neures.2020.07.006