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Pharmaceutics Oct 2022Three-dimensional (3D) printing is proving to be a pivotal technology for developing personalized dosage forms with bench to bedside feasibility. Fused deposition...
Three-dimensional (3D) printing is proving to be a pivotal technology for developing personalized dosage forms with bench to bedside feasibility. Fused deposition modelling (FDM) 3D printing has emerged as the most used technique wherein molten drug-loaded polymer filaments are deposited layer-by-layer to fabricate a predefined shape and internal geometry. However, for precise FDM 3D printing, it is imperative for the filaments to have peculiar mechanical/physicochemical properties, which the majority of the FDA/GRAS approved polymers lack. In the current study, a novel water-soluble polymer, Poly(2-ethyl-tetra-oxazoline) [PETOx] has been investigated as an extrudable and printable polymer with two different types of drug molecule—dextromethorphan hydrobromide (DXM) and hydrochlorothiazide (HCTZ). Hot-stage microscopy experiments of drug:polymer (1:1 w/w) and filaments were carried out at 25−275 °C. HCTZ-loaded filament showed higher toughness of 17 ± 3.25 × 106 J/m3 compared with DXM and drug-free filament. Moisture sorption and flexural analysis was performed to understand the correlation of mechanical properties and storage humidity to printability. Varying the number of outer perimeters of each layer (shell number) was observed to affect the drug release pattern from the printlets. The DXM one-shell printlet showed >80%, whereas the DXM five-shell printlet showed >60% of the drug release within 60 min. PETOx could prove to be a high-performance and versatile 3D printable polymer.
PubMed: 36297626
DOI: 10.3390/pharmaceutics14102192 -
International Journal of Molecular... Oct 2022This article presents a mechanism of action hypothesis to explain the rapid antidepressant effects of esmethadone (REL-1017) and other uncompetitive N-methyl-D-aspartate...
This article presents a mechanism of action hypothesis to explain the rapid antidepressant effects of esmethadone (REL-1017) and other uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists and presents a corresponding mechanism of disease hypothesis for major depressive disorder (MDD). Esmethadone and other uncompetitive NMDAR antagonists may restore physiological neural plasticity in animal models of depressive-like behavior and in patients with MDD via preferential tonic block of pathologically hyperactive GluN2D subtypes. Tonic Ca currents via GluN2D subtypes regulate the homeostatic availability of synaptic proteins. MDD and depressive behaviors may be determined by reduced homeostatic availability of synaptic proteins, due to upregulated tonic Ca currents through GluN2D subtypes. The preferential activity of low-potency NMDAR antagonists for GluN2D subtypes may explain their rapid antidepressant effects in the absence of dissociative side effects.
Topics: Animals; Depressive Disorder, Major; Receptors, N-Methyl-D-Aspartate; Antidepressive Agents; Neuronal Plasticity; Cell Communication
PubMed: 36293063
DOI: 10.3390/ijms232012196 -
Family Practice Mar 2023Despite the frequent use of symptomatic therapies in cough, evidence of their benefits is lacking. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Despite the frequent use of symptomatic therapies in cough, evidence of their benefits is lacking.
OBJECTIVE
We compared the effectiveness of 3 symptomatic therapies and usual care in acute bronchitis.
METHODS
Multicenter, pragmatic, multiarm parallel group, open randomized trial in primary care (ClinicalTrials.gov, Identifier: NCT03738917) was conducted in Catalonia. Patients ≥18 with uncomplicated acute bronchitis, with cough<3 weeks as the main symptom, scoring ≥4 in either daytime or nocturnal cough (7-point Likert scale), were randomized to usual care, dextromethorphan 15 mg t.i.d., ipratropium bromide inhaler 20 µg 2 puffs t.i.d, or 30 mg of honey t.i.d., all taken for up to 14 days. The main outcome measure was the number of days with moderate-to-severe cough. A symptom diary was given. A second visit was scheduled at days 2-3 for assessing evolution, with 2 more visits at days 15 and 29 for clinical assessment, evaluation of adverse effects, re-attendance, and complications.
RESULTS
We failed to achieve the sample size scheduled due to the COVID-19 pandemic. We finally recruited 194 patients. The median number of days with moderate-to-severe cough (score ≥ 3) in the usual care arm was 5 (interquartile range [IQR], 4, 8.75), 5 in the ipratropium bromide arm (IQR, 3, 8), 5 in the dextromethorphan arm (IQR, 4, 9.75), and 6 in the honey arm (IQR, 3.5, 7). The same results were obtained in the Kaplan-Meier survival analysis for the median survival time of each arm with the usual care as the reference group.
CONCLUSION
The symptomatic treatment evaluated has shown to be ineffective against cough.
Topics: Humans; Adult; Antitussive Agents; Cough; Dextromethorphan; Honey; Cholinergic Antagonists; Pandemics; COVID-19; Bronchitis; Ipratropium; Acute Disease
PubMed: 36239199
DOI: 10.1093/fampra/cmac112 -
Molecules (Basel, Switzerland) Oct 2022Common methodologies such as liquid-liquid extraction and solid-phase extraction are applied for the extraction of opioids from biological specimens i.e., blood and...
Common methodologies such as liquid-liquid extraction and solid-phase extraction are applied for the extraction of opioids from biological specimens i.e., blood and urine. Techniques including LC-MS/LC-MSMS, GC-MS, etc. are used for qualitative or quantitative determination of opioids. The goal of the present work is to design a green, economic, rugged, and simple extraction technique for famous opioids in human blood and urine and their simultaneous quantification by GC-MS equipped with an inert plus electron impact (EI) ionization source at SIM mode to produce reproducible and efficient results. Morphine, codeine, 6-acetylmorphine, nalbuphine, tramadol and dextromethorphan were selected as target opioids. Anhydrous Epsom salt was applied for dSPE of opioids from blood and urine into acetonitrile extraction solvent with the addition of sodium phosphate buffer (pH 6) and n-hexane was added to remove non-polar interfering species from samples. BSTFA was used as a derivatizing agent for GC-MS. Following method validation, the LOD/LLOQ and ULOQ were determined for morphine, codeine, nal-buphine, tramadol, and dextromethorphan at 10 ng/mL and 1500 ng/mL, respectively, while the LOD/LLOQ and ULOQ were determined for 6-acetylmorphine at 5 ng/mL and 150 ng/mL, respectively. This method was applied to real blood and urine samples of opioid abusers and the results were found to be reproducible with true quantification.
Topics: Acetonitriles; Analgesics, Opioid; Codeine; Dextromethorphan; Gas Chromatography-Mass Spectrometry; Humans; Morphine; Morphine Derivatives; Nalbuphine; Solid Phase Extraction; Solvents; Substance Abuse Detection; Tramadol
PubMed: 36235294
DOI: 10.3390/molecules27196761 -
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 -
American Journal of Alzheimer's Disease... 2022Dementia is one of neurodegenerative disease without preventive medicine currently. Dextromethorphan (DXM) has been reported to reduce neuronal damage and...
Dementia is one of neurodegenerative disease without preventive medicine currently. Dextromethorphan (DXM) has been reported to reduce neuronal damage and neurodegeneration in animal and human models. The effect of DXM on the dementia has not been fully examined. We examined the medical records over 40 years old in Taiwan's National Health Insurance Research Database between 2000 and 2015 to establish matched cohorts. We used a Cox regression hazard model to identify risk factors of dementia during 16 years of follow-up, and the results indicate that a significantly lower percentage of subjects with DXM use ( < .001) developed dementia compared with those without DXM use (11.38%, 4541/39 895 vs 18.66%, 29 785/159 580). After adjustment for age and other variables [adjusted hazard ratio: .567 (95% confidence interval: .413-.678, < .001)], this study also demonstrated that DXM use appeared to reduce the risk of developing dementia. DXM use may potentially provide a protective effect against dementia.
Topics: Adult; Animals; Dementia; Dextromethorphan; Humans; Neurodegenerative Diseases; Proportional Hazards Models; Risk Factors
PubMed: 36113413
DOI: 10.1177/15333175221124952 -
Frontiers in Pharmacology 2022The variant is the second or third frequent reduced function allele in Chinese with a frequency of around 3-4%, while it is the major reduced function allele in...
The variant is the second or third frequent reduced function allele in Chinese with a frequency of around 3-4%, while it is the major reduced function allele in Indians, Saudi Arabians and Caucasians with frequencies of around 10-20%. The present study was designed to explore the impact of on the metabolic activity of using phenotyping methods in urine, plasma, and saliva. We used dextromethorphan as the probe drug to analyze the phenotypes of 87 subjects with / ( = 22), / ( = 33), / ( = 4), / ( = 5), / ( = 3), / ( = 16), and / ( = 4) for . The ratio of parent drug to metabolite in 3 h saliva, 3 h plasma, and in 0-3 h urine was considered the metabolic ratio (MR). The allele had substantial impact on the metabolic activity of regardless of the urinary, plasma, or salivary phenotyping method used. In subjects with (or )/(or ), (or )/, / and / (all < 0.001), the salivary, plasma, or urinary MR value increased. The MRs in saliva, plasma, and urine displayed high correlations. The activity score system or the consensus activity score system, instead of the traditional phenotype classification, could predict the enzyme activity more accurately. had similar or more impact on the enzyme activity as compared with . Assigning a score of 0.5 and assigning a score of 0.25 according to the consensus AS system should be reconsidered.
PubMed: 36110554
DOI: 10.3389/fphar.2022.940510 -
BioMed Research International 2022Zuo-Gui Yin Decoction (ZGYD), a traditional Chinese prescription, is mainly used in various kinds of andrology and gynecology diseases. However, the study on the...
BACKGROUND
Zuo-Gui Yin Decoction (ZGYD), a traditional Chinese prescription, is mainly used in various kinds of andrology and gynecology diseases. However, the study on the interaction of ZGYD and drugs has not been reported. Therefore, evaluating the interaction between ZGYD and metabolic enzymes is helpful to guide rational drug use.
OBJECTIVE
This study was conducted to explore the effects of ZGYD on the activity and mRNA expressions of six Cytochrome P450 (CYP450) enzymes in rats and to provide a basis for its rational clinical use.
METHODS
Sprague-Dawley rats were randomly divided into control, ZGYD high, medium, and low-dose group ( = 6). The concentrations of six probe substrates in plasma of rats in each group were determined by UPLC-MS/MS. In addition, RT-PCR and Western blot were used to determine the effects of ZGYD on the expression of CYP450 isoforms in the liver.
RESULTS
Compared with the control group, the main pharmacokinetic parameters AUC, AUC , of omeprazole, dextromethorphan, and midazolam in the high-dose group were significantly decreased, while the CL of these were significantly increased. The gene expressions of CYP2C11 and CYP3A1 were upregulated in the ZGYD medium, high-dose group. The protein expression of CYP2C11 was upregulated in the high-dose group, and the protein expression of CYP3A1 was upregulated in the medium, high-dose group.
CONCLUSION
The results showed that ZGYD exhibited the induction effects on CYP2C11 and CYP3A1 (CYP2C19 and CYP3A4 in humans) in rats. However, no significant change in CYP1A2, CYP2B1, CYP2C7, and CYP2D2 activities was observed. It would be useful for the safe and effective usage of ZGYD in clinic.
Topics: Animals; Chromatography, High Pressure Liquid; Chromatography, Liquid; Cytochrome P-450 Enzyme System; Drugs, Chinese Herbal; Medicine, Chinese Traditional; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry
PubMed: 36060135
DOI: 10.1155/2022/4293062 -
Nature Cardiovascular Research Feb 2022Some missense gain-of-function mutations in gene, encoding calcium channel Ca1.2, cause a life-threatening form of long QT syndrome named Timothy syndrome, with...
Some missense gain-of-function mutations in gene, encoding calcium channel Ca1.2, cause a life-threatening form of long QT syndrome named Timothy syndrome, with currently no clinically-effective therapeutics. Here we report that pharmacological targeting of sigma non-opioid intracellular receptor 1 (SIGMAR1) can restore electrophysiological function in iPSC-derived cardiomyocytes generated from patients with Timothy syndrome and two common forms of long QT syndrome, type 1 (LQTS1) and 2 (LQTS2), caused by missense trafficking mutations in potassium channels. Electrophysiological recordings demonstrate that an FDA-approved cough suppressant, dextromethorphan, can be used as an agonist of SIGMAR1, to shorten the prolonged action potential in Timothy syndrome cardiomyocytes and human cellular models of LQTS1 and LQTS2. When tested , dextromethorphan also normalized the prolonged QT intervals in Timothy syndrome model mice. Overall, our study demonstrates that SIGMAR1 is a potential therapeutic target for Timothy syndrome and possibly other inherited arrhythmias such as LQTS1 and LQTS2.
PubMed: 36051854
DOI: 10.1038/s44161-021-00016-2 -
Pharmaceuticals (Basel, Switzerland) Aug 2022Excessive Ca currents via N-methyl-D-aspartate receptors (NMDARs) have been implicated in many disorders. Uncompetitive NMDAR channel blockers are an emerging class of...
Excessive Ca currents via N-methyl-D-aspartate receptors (NMDARs) have been implicated in many disorders. Uncompetitive NMDAR channel blockers are an emerging class of drugs in clinical use for major depressive disorder (MDD) and other neuropsychiatric diseases. The pharmacological characterization of uncompetitive NMDAR blockers in clinical use may improve our understanding of NMDAR function in physiology and pathology. REL-1017 (esmethadone-HCl), a novel uncompetitive NMDAR channel blocker in Phase 3 trials for the treatment of MDD, was characterized together with dextromethorphan, memantine, (±)-ketamine, and MK-801 in cell lines over-expressing NMDAR subtypes using fluorometric imaging plate reader (FLIPR), automated patch-clamp, and manual patch-clamp electrophysiology. In the absence of Mg, NMDAR subtypes NR1-2D were most sensitive to low, sub-μM glutamate concentrations in FLIPR experiments. FLIPR Ca determination demonstrated low μM affinity of REL-1017 at NMDARs with minimal subtype preference. In automated and manual patch-clamp electrophysiological experiments, REL-1017 exhibited preference for the NR1-2D NMDAR subtype in the presence of 1 mM Mg and 1 μM L-glutamate. Tau off and trapping characteristics were similar for (±)-ketamine and REL-1017. Results of radioligand binding assays in rat cortical neurons correlated with the estimated affinities obtained in FLIPR assays and in automated and manual patch-clamp assays. In silico studies of NMDARs in closed and open conformation indicate that REL-1017 has a higher preference for docking and undocking the open-channel conformation compared to ketamine. In conclusion, the pharmacological characteristics of REL-1017 at NMDARs, including relatively low affinity at the NMDAR, NR1-2D subtype preference in the presence of 1 mM Mg, tau off and degree of trapping similar to (±)-ketamine, and preferential docking and undocking of the open NMDAR, could all be important variables for understanding the rapid-onset antidepressant effects of REL-1017 without psychotomimetic side effects.
PubMed: 36015145
DOI: 10.3390/ph15080997