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MethodsX 2022The data presented in this article are related to the research article entitled "Cytochrome P450 inhibition activities of non-standardized botanical products" [1], in...
The data presented in this article are related to the research article entitled "Cytochrome P450 inhibition activities of non-standardized botanical products" [1], in which the possible CYP inhibitory properties of botanical products were investigated. This article describes the optimization and bioanalytical method validation of the CYP (Cytochrome P450 inhibition assay) inhibition assays, namely, phenacetin O-deethylase assay, testosterone 6β-hydroxylase assay, felodipine dehydrogenase assay and midazolam 1'-hydroxylase assay using LC-MS/MS.
PubMed: 36081487
DOI: 10.1016/j.mex.2022.101827 -
Molecules (Basel, Switzerland) Oct 2023Lekethromycin (LKMS) is a synthetic macrolide compound derivative intended for use as a veterinary medicine. Since there have been no in vitro studies evaluating its...
Lekethromycin (LKMS) is a synthetic macrolide compound derivative intended for use as a veterinary medicine. Since there have been no in vitro studies evaluating its potential for drug-drug interactions related to cytochrome P450 (CYP450) enzymes, the effect of the inhibitory mechanisms of LKMS on CYP450 enzymes is still unclear. Thus, this study aimed to evaluate the inhibitory effects of LKMS on dog CYP450 enzymes. A cocktail approach using ultra-performance liquid chromatography-tandem mass spectrometry was conducted to investigate the inhibitory effect of LKMS on canine CYP450 enzymes. Typical probe substrates of phenacetin, coumarin, bupropion, tolbutamide, dextromethorphan, chlorzoxazone, and testosterone were used for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4, respectively. This study showed that LKMS might not be a time-dependent inhibitor. LKMS inhibited CYP2A6, CYP2B6, and CYP2D6 via mixed inhibition. LKMS exhibited mixed-type inhibition against the activity of CYP2A6 with an inhibition constant (K) value of 135.6 μΜ. LKMS inhibited CYP2B6 in a mixed way, with K values of 59.44 μM. A phenotyping study based on an inhibition assay indicated that CYP2D6 contributes to the biotransformation of LKMS. A mixed inhibition of CYP2D6 with K values of 64.87 μM was also observed. Given that this study was performed in vitro, further in vivo studies should be conducted to identify the interaction between LKMS and canine CYP450 enzymes to provide data support for the clinical application of LKMS and the avoidance of adverse interactions between other drugs.
Topics: Dogs; Animals; Tandem Mass Spectrometry; Chromatography, Liquid; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP2D6; Microsomes, Liver; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Liver
PubMed: 37894672
DOI: 10.3390/molecules28207193 -
Forensic Science International Dec 2021Cocaine-related emergency department admissions are increasing, and cocaine seizures are at an all-time high in Europe. Our aim was to investigate the trends in purity...
Cocaine-related emergency department admissions are increasing, and cocaine seizures are at an all-time high in Europe. Our aim was to investigate the trends in purity and adulterants over time in cocaine available to cocaine users at street level in Denmark. We used a representative sample of cocaine seized at street level and analyzed by the national departments of forensic medicine between 2006 and 2019 (n = 1460). Latent profile analysis was used to classify the samples based on cocaine, levamisole, and phenacetin content. Low purity cocaine comprised most of the cocaine seizures in early years, but its share began to decline in 2013, and from 2016 to 2019, the high purity profile was dominant. While the total number of samples containing adulterants decreased, levamisole remained a common and dangerous adulterant. The findings underline the need to inform the public, medical doctors, and service providers for people with drug use disorders about the higher potency of street cocaine.
Topics: Cocaine; Denmark; Drug Contamination; Humans; Levamisole; Seizures
PubMed: 34736046
DOI: 10.1016/j.forsciint.2021.111050 -
Heliyon May 2024Medication overuse headache (MOH) is a secondary headache disorder that leads to pronounced disability and decreased quality of life. Available therapeutic options for...
BACKGROUND
Medication overuse headache (MOH) is a secondary headache disorder that leads to pronounced disability and decreased quality of life. Available therapeutic options for MOH are limited, and many are only effective in a subset of individuals. Although the existing evidence is limited, acupuncture may be an effective treatment option for MOH.
CASE PRESENTATION
A 45-year-old Chinese woman presented to the Medical Acupuncture Department of Sanming Integrated Traditional Chinese and Western Medicine Hospital on April 11, 2022. Thirty-five years ago, she had episodic migraines. The frequency increased over time, however, and for the past 10 years she has had daily headaches. These headaches were characterized by daily persistent throbbing pain on the left side of the patient's head, accompanied by photophobia, phonophobia, neck stiffness, dizziness, and fatigue. Without painkillers, the patient rated her headache intensity as 9 out of 10 on a visual analog scale (0 = no pain, 10 = intolerable pain), and reported that the headaches lasted for up to 7 days or more. With painkillers, the headaches had a reduced intensity (5 of 10), but persisted. The patient had taken 1-3.5 compound aminopyrine phenacetin tablets daily for more than 5 years. Standard conservative therapy (patient education, medication withdrawal, and behavioral intervention) for MOH had failed to improve her symptoms. Before her visit, the patient had headache and engaged in short-term medication use on 30 days per month. The total monthly headache intensity score was 90. The patient's Migraine-Specific Quality of Life Questionnaire (MSQ) score was 33 points, her Hamilton Depression Scale (HAMD) score was 24 points, and her Hamilton Anxiety Scale (HAMA) score was 20 points.
RESULTS
After 48 acupuncture sessions over 24 weeks, the patient completely discontinued short-term analgesic use and the monthly number of headache days and headache intensity score were both reduced by 96.67 % (from 30 to 1 and 90 to 3, respectively), with no adverse effect. Compared with baseline, the MSQ, HAMD, and HAMA scores improved by 45, 17, and 16 points, respectively. At 12 months, the patient's condition remained stable and her MOH had not relapsed.
CONCLUSION
In the context of the current literature and the present case, electroacupuncture shows promise for the long-term relief of chronic migraine with MOH when other treatments fail.
PubMed: 38720738
DOI: 10.1016/j.heliyon.2024.e30417 -
Drug Design, Development and Therapy 2021Avitinib is the first third-generation epithelial growth factor receptor (EGFR) inhibitor independently developed in China and is mainly used for treating non-small cell...
PURPOSE
Avitinib is the first third-generation epithelial growth factor receptor (EGFR) inhibitor independently developed in China and is mainly used for treating non-small cell lung cancer. However, pharmacokinetic details are limited. This study explored the in vivo and in vitro effects of avitinib on cytochrome CYP450 enzymes metabolic activity.
METHODS
A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for determining six probe substrates and their metabolites. Avitinib influence on activity levels of CYP isozymes was examined in vitro using human and rat liver microsomes (HLMs/RLMs). For in vivo studies, rats were pretreated with 30 mg/kg avitinib once daily for 7 days (avitinib multiple-doses group), 30 mg/kg avitinib on day 7 (avitinib single-dose group), or an equivalent amount of CMC-Na once daily for 7 days (control group), followed by intragastrical administration of the probe substrates (1 mg/kg tolbutamide and 10 mg/kg phenacetin, bupropion, chlorzoxazone, dextromethorphan, and midazolam). Plasma pharmacokinetics and IC values of the probe substrates were then compared. Pharmacokinetic parameters were determined using non-compartmental analysis implemented in a pharmacokinetic program.
RESULTS
In vitro experiments revealed different inhibitory effects of avitinib on the six probe substrates with various IC values (bupropion, 6.39/22.64 μM; phenacetin, 15.79/48.36 μM; chlorzoxazone, 23.15/57.09 μM; midazolam, 27.64/59.6 μM; tolbutamide, 42.18/6.91 μM; dextromethorphan, 44.39/56.57 μM, in RLMs and HLMs respectively). In vivo analysis revealed significant differences ( <0.05) in distinct pharmacokinetic parameters (AUC, AUC , C, MRT, MRT , and CLz/F) for the six probe substrates after avitinib pretreatment.
CONCLUSION
A sensitive and reliable UPLC-MS/MS method was established to determine the concentration of six probe substrates in rat plasma. Avitinib had inhibitory effects on CYP450 enzymes, especially cyp2b1, cyp1a2 in RLMs, CYP2C9 in HLMs, and cyp1a2, cyp2b1, cyp2d1, and cyp2e1 in vivo. Our data recommend caution when avitinib was taken simultaneously with drugs metabolized by CYP450 enzymes.
Topics: Animals; Area Under Curve; Chromatography, High Pressure Liquid; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Drug Interactions; Humans; Inhibitory Concentration 50; Male; Microsomes, Liver; Pharmaceutical Preparations; Protein Kinase Inhibitors; Pyrimidines; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Tandem Mass Spectrometry
PubMed: 34456561
DOI: 10.2147/DDDT.S323186 -
Materials (Basel, Switzerland) Jan 2024Acetaminophen (CHNO, also called paracetamol) is an active metabolite of phenacetin with antipyretic and analgesic effects and has been extensively used as a painkiller....
Acetaminophen (CHNO, also called paracetamol) is an active metabolite of phenacetin with antipyretic and analgesic effects and has been extensively used as a painkiller. Currently, the problem of pharmaceuticals in water and sewage is common, especially in highly urbanized countries. Laboratory-scale experiments were carried out using an adsorbent-granulated activated carbon (WD-extra)-to remove acetaminophen (ACT) from water. The initial concentration of acetaminophen was 20 mg ACT/dm. The adsorption kinetics, influence of the pH on adsorption and dose of the used adsorbent were determined under batch conditions. The adsorption of ACT on activated carbon was more efficient when the water solution was acidic (at pH 2, it was the most effective). The highest percentage of removal (99%) was obtained for the WD-extra dose of 10.0 g/dm. The time taken to establish the dynamic equilibrium of the system was 60 min. The effectiveness of adsorption was determined based on the Freundlich and Langmuir adsorption isotherms. It was found that WD-extra activated carbon effectively removed ACT from water solutions.
PubMed: 38255599
DOI: 10.3390/ma17020431 -
Frontiers in Cell and Developmental... 2021Gliomas are highly lethal brain tumors. Despite multimodality therapy with surgery, radiotherapy, chemotherapy, and immunotherapy, glioma prognosis remains poor....
Gliomas are highly lethal brain tumors. Despite multimodality therapy with surgery, radiotherapy, chemotherapy, and immunotherapy, glioma prognosis remains poor. Ferroptosis is a crucial tumor suppressor mechanism that has been proven to be effective in anticancer therapy. However, the implications of ferroptosis on the clinical prognosis, chemotherapy, and immune checkpoint inhibitor (ICI) therapy for patients with glioma still need elucidation. Consensus clustering revealed two distinct ferroptosis-related subtypes based on the Cancer Genome Atlas (TCGA) glioma dataset ( = 663). Subsequently, the ferroptosis-related gene prognostic index (FRGPI) was constructed by weighted gene co-expression network analysis (WGCNA) and "stepAIC" algorithms and validated with the Chinese Glioma Genome Atlas (CGGA) dataset ( = 404). Subsequently, the correlation among clinical, molecular, and immune features and FRGPI was analyzed. Next, the temozolomide sensitivity and ICI response for glioma were predicted using the "pRRophetic" and "TIDE" algorithms, respectively. Finally, candidate small molecular drugs were defined using the connectivity map database based on FRGPI. The FRGPI was established based on the , , , and genes. The distribution of FRGPI varied significantly among the different ferroptosis-related subtypes. Patients with high FRGPI had a worse overall prognosis than patients with low FRGPI, consistent with the results in the CGGA dataset. The final results showed that high FRGPI was characterized by more aggressive phenotypes, high expression, high tumor mutational burden score, and enhanced temozolomide sensitivity; low FRGPI was associated with less aggressive phenotypes, high microsatellite instability score, and stronger response to immune checkpoint blockade. In addition, the infiltration of memory resting CD4 T cells, regulatory T cells, M1 macrophages, M2 macrophages, and neutrophils was positively correlated with FRGPI. In contrast, plasma B cells and naïve CD4 T cells were negatively correlated. A total of 15 potential small molecule compounds (such as depactin, physostigmine, and phenacetin) were identified. FRGPI is a promising gene panel for predicting the prognosis, immune characteristics, temozolomide sensitivity, and ICI response in patients with glioma.
PubMed: 35174170
DOI: 10.3389/fcell.2021.812422 -
Frontiers in Microbiology 2022Mycotoxins, fungal secondary metabolites, are ubiquitously present in food commodities. Acute exposure to high levels or chronic exposure to low levels has an impact on...
Unravelling the pharmacokinetics of aflatoxin B1: determination of Michaelis-Menten constants, intrinsic clearance and the metabolic contribution of CYP1A2 and CYP3A4 in pooled human liver microsomes.
Mycotoxins, fungal secondary metabolites, are ubiquitously present in food commodities. Acute exposure to high levels or chronic exposure to low levels has an impact on the human body. The phase I metabolism in the human liver, performed by cytochrome P450 (CYP450) enzymes, is accountable for more than 80% of the overall metabolism of exogenous and endogenous compounds. Mycotoxins are (partially) metabolized by CYP450 enzymes. In this study, research was performed on CYP450 probes and aflatoxin B1 (AFB1), a carcinogenic mycotoxin, to obtain pharmacokinetic data on AFB1, required for further experimental work. The CYP450 probes of choice were a CYP3A4 substrate, midazolam (MDZ) and a CYP1A2 substrate, phenacetin (PH) since these are the main metabolizing phase I enzymes of AFB1. Linearity experiments were performed on the three substrates indicating that linear conditions were achieved at a microsomal protein concentration and incubation time of 0.25 mg/ml and 5 min, 0.50 mg/ml and 20 min and 0.25 mg/ml and 5 min for MDZ, PH and AFB1, respectively. The was determined in human liver microsomes and was estimated at 2.15 μM for MDZ, 40.0 μM for PH and 40.9 μM for AFB1. The associated values were 956 pmol/(mg.min) (MDZ), 856 pmol/(mg.min) (PH) and 11,536 pmol/(mg.min) (AFB1). Recombinant CYP systems were used to determine CYP450-specific Michaelis-Menten values for AFB1, leading to a CYP3A4 of 49.6 μM and an intersystem extrapolation factor (ISEF) corrected of 43.6 pmol/min/pmol P450 and a CYP1A2 of 58.2 μM and an ISEF corrected of 283 pmol/min/pmol P450. An activity adjustment factor (AAF) was calculated to account for differences between microsome batches and was used as a correction factor in the determination of the human hepatic clearance for MDZ, PH and AFB1. The hepatic blood clearance corrected for the AAF CL, CL CL and CL were determined in HLM at 44.1 L/h, 21.7 L/h, 40.0 L/h and 38.5 L/h. Finally, inhibition assays in HLM showed that 45% of the AFB1 metabolism was performed by CYP3A4/3A5 enzymes and 49% by CYP1A2 enzymes.
PubMed: 36110298
DOI: 10.3389/fmicb.2022.988083 -
IUCrJ May 2021As the first step in the crystallization process, nucleation has been studied by many researchers. In this work, phenacetin (PHEN) was selected as a model compound to...
As the first step in the crystallization process, nucleation has been studied by many researchers. In this work, phenacetin (PHEN) was selected as a model compound to investigate the relationship between the solvent and nucleation kinetics. Induction times at different supersaturation in six solvents were measured. FTIR and NMR spectroscopy were employed to explore the solvent-solute interactions and the self-association properties in solution. Density functional theory (DFT) was adopted to evaluate the strength of solute-solvent interactions and the molecular conformations in different solvents. Based on these spectroscopy data, molecular simulation and nucleation kinetic results, a comprehensive understanding of the relationship between molecular structure, crystal structure, solution chemistry and nucleation dynamics is discussed. Both the solute-solvent interaction strength and the supramolecular structure formed by the self-association of solute molecules affect the nucleation rate. The findings reported here shed new light on the molecular mechanism of nucleation in solution.
PubMed: 33953933
DOI: 10.1107/S2052252521003882 -
Clinical Toxicology (Philadelphia, Pa.) Sep 2022Novel opioids in the illicit drug supply, such as the "nitazene" group of synthetic opioids, present an ongoing public health problem due to high potency and respiratory...
BACKGROUND
Novel opioids in the illicit drug supply, such as the "nitazene" group of synthetic opioids, present an ongoing public health problem due to high potency and respiratory depressant effects. We describe three patients in whom -piperidinyl etonitazene, a compound not previously reported in human exposure, was detected after suspected opioid overdose. Other substances that these patients tested for included fentanyl, cocaine, levamisole, phenacetin, benzoylecgonine, -fluorofentanyl, presumptive heroin (tested as 6-monoacetylmorphine (6-MAM), morphine, and codeine), and tramadol.
METHODS
This is a case series of patients with acute opioid overdose enrolled in an ongoing multicenter prospective cohort study. Data collected included reported substance use, clinical course, naloxone dose and response, outcome, and analytes detected in biological samples.
RESULTS
Between October 6, 2020 and October 31, 2021, 1006 patients were screened and 412 met inclusion criteria. Of these, three patients (age 33-55) tested positive for -piperidinyl etonitazene at one site in New Jersey over a period of three days in July 2021. Two patients reported the use of cocaine; one reported the use of heroin and alprazolam. All three patients received naloxone with improvement in their mental status (2 milligrams (mg) intranasally (IN); 8 mg IN; 0.08 mg intravenous (IV)). Two of three received subsequent doses for recurrence of opioid toxicity (0.4-0.6 mg IV). One patient was diagnosed with pneumonia and admitted to the intensive care unit, one was discharged from the Emergency Department (ED), and one used additional drug while in the ED and required admission for a naloxone infusion. None developed organ damage or sequelae.
CONCLUSION
These cases represent a local outbreak of a novel "nitazene" opioid. Public health toxicosurveillance should incorporate routine testing of this emerging class of synthetic compounds in the illicit drug supply.
Topics: Adult; Alprazolam; Analgesics, Opioid; Benzimidazoles; Cocaine; Codeine; Drug Overdose; Fentanyl; Heroin; Humans; Illicit Drugs; Levamisole; Middle Aged; Naloxone; Narcotic Antagonists; Opiate Overdose; Phenacetin; Prospective Studies; Tramadol
PubMed: 35708103
DOI: 10.1080/15563650.2022.2084406