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Frontiers in Pharmacology 2023Vortioxetine is a novel anti-major depression disorder drug with a high safety profile compared with other similar drugs. However, little research has been done on...
Vortioxetine is a novel anti-major depression disorder drug with a high safety profile compared with other similar drugs. However, little research has been done on drug-drug interactions (DDI) about vortioxetine. In this paper, the inhibitory effect of vortioxetine on cytochrome P450 (CYP450) and the type of inhibitory mechanism were investigated in human and rat liver microsomes. We set up an incubation system of 200 μL to measure the metabolism of probe substrates at the present of vortioxetine at 37°C. The concentrations of the metabolites of probe substrates were all measured by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. It was found no time-dependent inhibition (TDI) of vortioxetine through determination of half-maximal inhibitory concentration (IC) shift values. The enzymes and metabolites involved in this experiment in human and rats were as follows: CYP3A4/CYP3A (midazolam); CYP2B6/CYP2B (bupropion); CYP2D6/CYP2D (dextromethorphan); CYP2C8/CYP2C-1 (amodiaquine); CYP2C9/CYP2C-2 (losartan); and CYP2C19/CYP2C-3 (mephenytoin). We found that vortioxetine competitively inhibited CYP2C19 and CYP2D6 in human liver microsomes (HLMs) with inhibition constant (K) values of 2.17 μM and 9.37 μM, respectively. It was noncompetitive inhibition for CYP3A4 and CYP2C8, and its K values were 7.26 μM and 6.96 μM, respectively. For CYP2B6 and CYP2C9, vortioxetine exhibited the mixed inhibition with K values were 8.55 μM and 4.17 μM, respectively. In RLMs, the type of vortioxetine inhibition was uncompetitive for CYP3A and CYP2D (K = 4.41 and 100.9 μM). The inhibition type was competitive inhibition, including CYP2B and CYP2C-2 (K = 2.87 and 0.12 μM). The inhibition types of CYP2C-1 and CYP2C-3 (K = 39.91 and 4.23 μM) were mixed inhibition and noncompetitive inhibition, respectively. The study of the above mechanism will provide guidance for the safe clinical use of vortioxetine so that the occurrence of DDI can be avoided.
PubMed: 37790811
DOI: 10.3389/fphar.2023.1199548 -
Current Treatment Options in Psychiatry Dec 2020Neuropsychiatric symptoms are universal across all stages and types of dementia and can cause significant challenges for patients and caregivers. While there are...
PURPOSE
Neuropsychiatric symptoms are universal across all stages and types of dementia and can cause significant challenges for patients and caregivers. While there are currently no approved medications for treatment of neuropsychiatric symptoms of dementia, a variety of psychotropic medications such as antipsychotics, benzodiazepines, anticonvulsants, and antidepressants are used off-label to treat these symptoms. This systematic review evaluated the available evidence for effectiveness and tolerability of pharmacologic treatments in addressing behavioral disturbances in dementia.
RECENT FINDINGS
Inclusion criteria were placebo-controlled, randomized controlled clinical trials (RCTs) or meta-analyses; a total of 38 studies and 3 meta-analyses representing an additional 27 RCTs met the inclusion criteria. Of the medication classes evaluated, atypical antipsychotics had the greatest available evidence for use, however, the treatment effect size was modest. Nine trials of antidepressants were included; 3 trials supported use in dementia. Eight trials of anticonvulsants were included; only one showed benefit. For benzodiazepines, 2 RCTs were included; only one trial of lorazepam showed improvement. Six trials of melatonin agonists were included; none showed efficacy outside of improved sleep measures. Evidence for effectiveness of pimavanserin and dextromethorphan-quinidine was limited to one study each, both of which showed benefit.
SUMMARY
Despite the widespread off-label use of psychotropic medications for treatment of neuropsychiatric symptoms in dementia, there are relatively few RCTs to evaluate their use with treatment effect sizes absent or modest for most medication classes. Of the medication classes reviewed, atypical antipsychotics have the best evidence for effectiveness, however, the overall magnitude of treatment effect is modest and must be balanced with risk of serious adverse events including death.
PubMed: 33344107
DOI: 10.1007/s40501-020-00233-9 -
Arquivos de Neuro-psiquiatria Aug 2023The spectrum of neuropsychiatric phenomena observed in amyotrophic lateral sclerosis (ALS) is wide and not fully understood. Disorders of laughter and crying stand among...
Definitions, phenomenology, diagnosis, and management of the disorders of laughter and crying in amyotrophic lateral sclerosis (ALS): Consensus from ALS and Motor Neuron Disease Scientific Department of the Brazilian Academy of Neurology.
The spectrum of neuropsychiatric phenomena observed in amyotrophic lateral sclerosis (ALS) is wide and not fully understood. Disorders of laughter and crying stand among the most common manifestations. The aim of this study is to report the results of an educational consensus organized by the Brazilian Academy of Neurology to evaluate the definitions, phenomenology, diagnosis, and management of the disorders of laughter and crying in ALS patients. Twelve members of the Brazilian Academy of Neurology - considered to be experts in the field - were recruited to answer 12 questions about the subject. After exchanging revisions, a first draft was prepared. A face-to-face meeting was held in Fortaleza, Brazil on 9.23.22 to discuss it. The revised version was subsequently emailed to all members of the ALS Scientific Department from the Brazilian Academy of Neurology and the final revised version submitted for publication. The prevalence of pseudobulbar affect/pathological laughter and crying (PBA/PLC) in ALS patients from 15 combined studies and 3906 patients was 27.4% ( = 1070), ranging from 11.4% to 71%. Bulbar onset is a risk factor but there are limited studies evaluating the differences in prevalence among the different motor neuron diseases subtypes, including patients with and without frontotemporal dementia. Antidepressants and a combination of dextromethorphan and quinidine (not available in Brazil) are possible therapeutic options. This group of panelists acknowledge the multiple gaps in the current literature and reinforces the need for further studies.
Topics: Humans; Amyotrophic Lateral Sclerosis; Brazil; Laughter; Consensus; Crying; Motor Neuron Disease; Neurology
PubMed: 37647907
DOI: 10.1055/s-0043-1771176 -
Translational Psychiatry Jun 2023Esmethadone (REL-1017) is the opioid-inactive dextro-isomer of methadone and a low-affinity, low-potency uncompetitive NMDA receptor antagonist. In a Phase 2,... (Randomized Controlled Trial)
Randomized Controlled Trial
Esmethadone (REL-1017) is the opioid-inactive dextro-isomer of methadone and a low-affinity, low-potency uncompetitive NMDA receptor antagonist. In a Phase 2, randomized, double-blind, placebo-controlled trial, esmethadone showed rapid, robust, and sustained antidepressant effects. Two studies were conducted to evaluate the abuse potential of esmethadone. Each study utilized a randomized, double-blind, active-, and placebo-controlled crossover design to assess esmethadone compared with oxycodone (Oxycodone Study) or ketamine (Ketamine Study) in healthy recreational drug users. Esmethadone 25 mg (proposed therapeutic daily dose), 75 mg (loading dose), and 150 mg (Maximum Tolerated Dose) were evaluated in each study. Positive controls were oral oxycodone 40 mg and intravenous ketamine 0.5 mg/kg infused over 40 min. The Ketamine study included oral dextromethorphan 300 mg as an exploratory comparator. The primary endpoint was maximum effect (E) for Drug Liking, assessed using a bipolar 100-point visual analog scale (VAS). A total of 47 and 51 participants completed the Oxycodone Study and the Ketamine Study, respectively (Completer Population). In both studies, esmethadone doses ranging from therapeutic (25 mg) to 6 times therapeutic (150 mg) had a meaningful and statistically significantly (p < 0.001) lower Drug Liking VAS E compared with the positive control. Results were consistent for all secondary endpoints in both studies. In both studies, all doses of esmethadone were statistically equivalent to placebo on Drug Liking VAS E (p < 0.05). In the Ketamine Study, Drug Liking VAS E scores for esmethadone at all tested doses were significantly lower vs. dextromethorphan (p < 0.05) (exploratory endpoint). These studies indicate no meaningful abuse potential for esmethadone at all tested doses.
Topics: Humans; Oxycodone; Receptors, N-Methyl-D-Aspartate; Dextromethorphan; Ketamine; Analgesics, Opioid; Cross-Over Studies; Double-Blind Method; Illicit Drugs
PubMed: 37286536
DOI: 10.1038/s41398-023-02473-8 -
Nature Genetics Feb 2023Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide...
Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.
Topics: Humans; Transcriptome; Drug Repositioning; Genome-Wide Association Study; Tobacco Use; Biology; Polymorphism, Single Nucleotide; Genetic Predisposition to Disease
PubMed: 36702996
DOI: 10.1038/s41588-022-01282-x -
The Journal of Pharmacology and... Jan 2021Preparations from the leaves of the kratom plant () are consumed for their opioid-like effects. Several deaths have been associated with kratom used concomitantly with...
Preparations from the leaves of the kratom plant () are consumed for their opioid-like effects. Several deaths have been associated with kratom used concomitantly with some drugs. Pharmacokinetic interactions are potential underlying mechanisms of these fatalities. Accumulating in vitro evidence has demonstrated select kratom alkaloids, including the abundant indole alkaloid mitragynine, as reversible inhibitors of several cytochromes P450 (CYPs). The objective of this work was to refine the mechanistic understanding of potential kratom-drug interactions by considering both reversible and time-dependent inhibition (TDI) of CYPs in the liver and intestine. Mitragynine was tested against CYP2C9 (diclofenac 4'-hydroxylation), CYP2D6 (dextromethorphan -demethylation), and CYP3A (midazolam 1'-hydroxylation) activities in human liver microsomes (HLMs) and CYP3A activity in human intestinal microsomes (HIMs). Comparing the absence to presence of NADPH during preincubation of mitragynine with HLMs or HIMs, an ∼7-fold leftward shift in IC (∼20 to 3 μM) toward CYP3A resulted, prompting determination of TDI parameters (HLMs: , 4.1 ± 0.9 μM; , 0.068 ± 0.01 min; HIMs: , 4.2 ± 2.5 μM; , 0.079 ± 0.02 min). Mitragynine caused no leftward shift in IC toward CYP2C9 (∼40 μM) and CYP2D6 (∼1 μM) but was a strong competitive inhibitor of CYP2D6 ( , 1.17 ± 0.07 μM). Using a recommended mechanistic static model, mitragynine (2-g kratom dose) was predicted to increase dextromethorphan and midazolam area under the plasma concentration-time curve by 1.06- and 5.69-fold, respectively. The predicted midazolam area under the plasma concentration-time curve ratio exceeded the recommended cutoff (1.25), which would have been missed if TDI was not considered. SIGNIFICANCE STATEMENT: Kratom, a botanical natural product increasingly consumed for its opioid-like effects, may precipitate potentially serious pharmacokinetic interactions with drugs. The abundant kratom indole alkaloid mitragynine was shown to be a time-dependent inhibitor of hepatic and intestinal cytochrome P450 3A activity. A mechanistic static model predicted mitragynine to increase systemic exposure to the probe drug substrate midazolam by 5.7-fold, necessitating further evaluation dynamic models and clinical assessment to advance the understanding of consumer safety associated with kratom use.
Topics: Cytochrome P450 Family 2; Dextromethorphan; Drug Interactions; Humans; Intestinal Mucosa; Microsomes, Liver; Midazolam; Secologanin Tryptamine Alkaloids
PubMed: 33093187
DOI: 10.1124/jpet.120.000270 -
BMC Nephrology Sep 2020This study aimed to understand the mechanistic role of N-methyl-D-aspartate receptor (NMDAR) in acute fibrogenesis using models of in vivo ureter obstruction and in...
BACKGROUND
This study aimed to understand the mechanistic role of N-methyl-D-aspartate receptor (NMDAR) in acute fibrogenesis using models of in vivo ureter obstruction and in vitro TGF-β administration.
METHODS
Acute renal fibrosis (RF) was induced in mice by unilateral ureteral obstruction (UUO). Histological changes were observed using Masson's trichrome staining. The expression levels of NR1, which is the functional subunit of NMDAR, and fibrotic and epithelial-to-mesenchymal transition markers were measured by immunohistochemical and Western blot analysis. HK-2 cells were incubated with TGF-β, and NMDAR antagonist MK-801 and Ca/calmodulin-dependent protein kinase II (CaMKII) antagonist KN-93 were administered for pathway determination. Chronic RF was introduced by sublethal ischemia-reperfusion injury in mice, and NMDAR inhibitor dextromethorphan hydrobromide (DXM) was administered orally.
RESULTS
The expression of NR1 was upregulated in obstructed kidneys, while NR1 knockdown significantly reduced both interstitial volume expansion and the changes in the expression of α-smooth muscle actin, S100A4, fibronectin, COL1A1, Snail, and E-cadherin in acute RF. TGF-β1 treatment increased the elongation phenotype of HK-2 cells and the expression of membrane-located NR1 and phosphorylated CaMKII and extracellular signal-regulated kinase (ERK). MK801 and KN93 reduced CaMKII and ERK phosphorylation levels, while MK801, but not KN93, reduced the membrane NR1 signal. The levels of phosphorylated CaMKII and ERK also increased in kidneys with obstruction but were decreased by NR1 knockdown. The 4-week administration of DXM preserved renal cortex volume in kidneys with moderate ischemic-reperfusion injury.
CONCLUSIONS
NMDAR participates in both acute and chronic renal fibrogenesis potentially via CaMKII-induced ERK activation.
Topics: Animals; Benzylamines; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Dextromethorphan; Dizocilpine Maleate; Epithelial-Mesenchymal Transition; Excitatory Amino Acid Antagonists; Fibrosis; Gene Knockdown Techniques; Humans; In Vitro Techniques; Kidney; Kidney Tubules, Proximal; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Protein Kinase Inhibitors; Receptors, N-Methyl-D-Aspartate; Renal Insufficiency, Chronic; Reperfusion Injury; Sulfonamides; Transforming Growth Factor beta; Ureteral Obstruction
PubMed: 32907546
DOI: 10.1186/s12882-020-02050-x -
International Journal of Molecular... Oct 2022Metabolic associated fatty liver disease (MAFLD) is the most common chronic liver disease, with an estimated prevalence of between 20 and 30% worldwide. Observational... (Meta-Analysis)
Meta-Analysis Review
Metabolic associated fatty liver disease (MAFLD) is the most common chronic liver disease, with an estimated prevalence of between 20 and 30% worldwide. Observational data supported by in vitro and pre-clinical animal models of MAFLD suggest meaningful differences in drug disposition in MAFLD patients. This study aimed to build a physiologically based pharmacokinetic (PBPK) model reflecting observed changes in physiological and molecular parameters relevant to drug disposition that are associated with MAFLD. A comprehensive literature review and meta-analysis was conducted to identify all studies describing in vivo physiological changes along with in vitro and pre-clinical model changes in CYP 1A2, 2C9, 2C19, 2D6 and 3A4 protein abundance associated with MAFLD. A MAFLD population profile was constructed in Simcyp (version 19.1) by adapting demographic and physiological covariates from the Sim-Healthy population profile based on a meta-analysis of observed data from the published literature. Simulations demonstrated that single dose and steady state area under the plasma concentration time curve (AUC) for caffeine, clozapine, omeprazole, metoprolol, dextromethorphan and midazolam, but not s-warfarin or rosiglitazone, were increased by >20% in the MAFLD population compared to the healthy control population. These findings indicate that MAFLD patients are likely to be experience meaningfully higher exposure to drugs that are primarily metabolized by CYP 1A2, 2C19, 2D6 and 3A4, but not CYP2C9. Closer monitoring of MAFLD patients using drugs primarily cleared by CYP 1A2, 2C19 and 3A4 is warranted as reduced metabolic activity and increased drug exposure are likely to result in an increased incidence of toxicity in this population.
Topics: Animals; Caffeine; Clozapine; Cytochrome P-450 CYP1A2; Cytochrome P-450 Enzyme System; Dextromethorphan; Metoprolol; Midazolam; Non-alcoholic Fatty Liver Disease; Omeprazole; Rosiglitazone; Warfarin
PubMed: 36233052
DOI: 10.3390/ijms231911751 -
Briefings in Bioinformatics May 2022Inhibition of host protein functions using established drugs produces a promising antiviral effect with excellent safety profiles, decreased incidence of resistant...
Inhibition of host protein functions using established drugs produces a promising antiviral effect with excellent safety profiles, decreased incidence of resistant variants and favorable balance of costs and risks. Genomic methods have produced a large number of robust host factors, providing candidates for identification of antiviral drug targets. However, there is a lack of global perspectives and systematic prioritization of known virus-targeted host proteins (VTHPs) and drug targets. There is also a need for host-directed repositioned antivirals. Here, we integrated 6140 VTHPs and grouped viral infection modes from a new perspective of enriched pathways of VTHPs. Clarifying the superiority of nonessential membrane and hub VTHPs as potential ideal targets for repositioned antivirals, we proposed 543 candidate VTHPs. We then presented a large-scale drug-virus network (DVN) based on matching these VTHPs and drug targets. We predicted possible indications for 703 approved drugs against 35 viruses and explored their potential as broad-spectrum antivirals. In vitro and in vivo tests validated the efficacy of bosutinib, maraviroc and dextromethorphan against human herpesvirus 1 (HHV-1), hepatitis B virus (HBV) and influenza A virus (IAV). Their drug synergy with clinically used antivirals was evaluated and confirmed. The results proved that low-dose dextromethorphan is better than high-dose in both single and combined treatments. This study provides a comprehensive landscape and optimization strategy for druggable VTHPs, constructing an innovative and potent pipeline to discover novel antiviral host proteins and repositioned drugs, which may facilitate their delivery to clinical application in translational medicine to combat fatal and spreading viral infections.
Topics: Antiviral Agents; Dextromethorphan; Humans; Influenza A virus
PubMed: 35238349
DOI: 10.1093/bib/bbac047 -
International Journal of Clinical... 2020To compare the cariogenic and erosive potential of seven commonly prescribed pediatric liquid medicaments (PLMs) by pediatricians in Kempegowda Institute of Medical...
AIM
To compare the cariogenic and erosive potential of seven commonly prescribed pediatric liquid medicaments (PLMs) by pediatricians in Kempegowda Institute of Medical Sciences, Bengaluru. The selected medicaments are:Syp paracetamol (antipyretic).Syp amoxicillin-clavulanate (antibiotic).Syp cetirizine (antihistamine).Syp dextromethorphan (antitussive).Syp salbutamol (antiasthmatic).Syp phenytoin (anticonvulsant).Syp multivitamin (nutritional supplement).
MATERIALS AND METHODS
Quantitative endogenous sucrose estimation: Lane-Eynon volumetric copper reduction method was used for the estimation.Endogenous pH estimation: The endogenous pH was measured using a digital pH meter at 10% dilution.Quantification of endogenous erosive potential: few caries and restoration-free, exfoliated or extracted primary teeth were utilized to produce 1-1.5 g of enamel powder. A 50 mg of enamel powder was then added to 1 mL of individual PLM. The mixtures were maintained for three-time intervals, 1 minute, 10 minutes, and 8 hours. The samples were then prepared for the estimation of calcium using Inductively Coupled Plasma Mass Spectrometry.
RESULTS
Sucrose was seen in all the PLMs except amoxicillin-clavulanate. Calcium was found to be present in all the PLMs except cetirizine. The highest calcium dissolution was seen within Syp salbutamol and the least with Syp paracetamol.
CONCLUSION
Syp phenytoin can be regarded as medicament with the highest cariogenic potential and Syp salbutamol with the highest erosive potential and Syp paracetamol with the lowest cariogenic and erosive potential among the compared and tested PLMs.
CLINICAL SIGNIFICANCE
Considering syrups that have high cariogenic and erosive potential, greater knowledge about the detrimental effects of these drugs should direct us to evolve effective programs to alert parents to follow proper oral hygiene practices or to search for alternative drugs void of such detrimental effects.
HOW TO CITE THIS ARTICLE
Singana T, Suma NK. An Assessment of Cariogenic and Erosive Potential of Pediatric Liquid Medicaments on Primary Teeth: A Comparative Study. Int J Clin Pediatr Dent 2020;13(6):595-599.
PubMed: 33976481
DOI: 10.5005/jp-journals-10005-1824