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Evidence-based Complementary and... 2019Naoxintong capsule (NXT), a prescribed Chinese medicine, has been used clinically for more than 20 years and is widely received by patients. We determined five probe...
Naoxintong capsule (NXT), a prescribed Chinese medicine, has been used clinically for more than 20 years and is widely received by patients. We determined five probe drugs, namely, omeprazole (CYP2C19), midazolam (CYP3A4), phenacetin (CYP1A2), tolbutamide (CYP2C9), and dextromethorphan (CYP2D6) to study the potential influences of NXT on the activities of CYP enzymes and assessed the pharmacokinetics effect of NXT on metoprolol tartrate in rat plasma. The study showed that AUC and AUC of midazolam (CYP3A4) in NXT coadministration group (283.7 ± 65.2 h·ng·mL and 292.0 ± 75.1 h·ng·mL in group B; 295.7 ± 62.7 h·ng·mL and 299.5 ± 60.0 h·ng·mL in group C) were significantly decreased as compared to another group (416.8 ± 82.3 h·ng·mL and 424.9 ± 77.9 h·ng·mL in group A), while that of dextromethorphan (CYP2D6) showed an opposite tendency (540.7 ± 119.7 h·ng·mL and 595.3 ± 122.2 h·ng·mL in group A, 760.6 ± 184.9 h·ng·mL and 788.7 ± 211.0 h·ng·mL in group B, and 734.3 ± 118.5 h·ng·mL and 757.2 ± 105.4 h·ng·mL in group C). Moreover, NXT preadministration can enhance the metabolism of metoprolol tartrate and reduce the metabolism of O-demethylmetoprolol. The results indicated that NXT had potential effects in inducing CYP3A4 and inhibiting CYP2D6 in the metabolism of metoprolol tartrate. It suggests that patients who coadministered NXT and metoprolol tartrate should be advised of potential herb-drug interactions (HDIs) to reduce therapeutic failure or accelerated toxicity of conventional drug treatment.
PubMed: 31662775
DOI: 10.1155/2019/5242605 -
ACS Omega Oct 2019A new method of data interpretation based on classical nucleation theory is proposed in this work to elucidate the influence of solvents on the pre-exponential...
A new method of data interpretation based on classical nucleation theory is proposed in this work to elucidate the influence of solvents on the pre-exponential nucleation factor and interfacial energy using the induction time data for three crystallization systems, including isonicotinamide, lovastatin, and phenacetin. In this method, the pre-exponential nucleation factor is replaced by the intrinsic nucleation factor multiplied by temperature and divided by solution viscosity. The proposed method is applied to study the nucleation kinetics of isonicotinamide, lovastatin, and phenacetin among various solvents using the induction time data measured in this work. The results indicate that the intrinsic nucleation factor increases linearly with increasing square root of interfacial energy in various solvents for each system.
PubMed: 31656908
DOI: 10.1021/acsomega.9b02102 -
Biological & Pharmaceutical Bulletin Jan 2020To improve the efficiency of drug-discovery research on pyrrole-imidazole polyamides (PIs), a more rapid method for quantitative and qualitative measurement of PI in rat...
To improve the efficiency of drug-discovery research on pyrrole-imidazole polyamides (PIs), a more rapid method for quantitative and qualitative measurement of PI in rat plasma samples was developed here using ultra-fast liquid chromatography-ultraviolet spectrometry (UFLC-UV) in order to shorten the measurement time. A measurement method of PIs by HPLC developed until now takes 45 min for one sample measurement. This method was inefficient to investigate extraction conditions from biological samples and measurement of animal experimental samples. In the developed method of this study, PI and phenacetin (internal standard, IS) were separated with an ACQUITY UPLC HSS T3 (1.8 µm, 2.1 × 50 mm; Nihon Waters K.K., Japan) column using a mobile phase of 0.1% acetic acid (mobile phase A) and acetonitrile (mobile phase B) at a flow rate of 0.3 mL/min with a linear gradient. The detection wavelength was 310 nm. The calibration curve was linear in the range of 0.225-4.5 µg/mL (correlation coefficients ≥0.9995, n = 5). The intra- and inter-day accuracies were in the range of -6.04 to 12.2%, and the precision was less than 2.99%. The measurement time of this method (7 min per injection) was markedly shortened to about one-sixth of the previous measurement time (45 min per injection). This is the first report describing the quantitative and qualitative measurement of PI in plasma using UFLC-UV. The present method will be very useful for the drug-discovery research of PIs.
Topics: Animals; Calibration; Chromatography, High Pressure Liquid; Imidazoles; Male; Molecular Structure; Pyrroles; Rats, Sprague-Dawley; Reference Standards; Reproducibility of Results; Spectrophotometry, Ultraviolet
PubMed: 31645526
DOI: 10.1248/bpb.b19-00644 -
Molecules (Basel, Switzerland) Sep 2019Cytochromes P450 are major metabolic enzymes involved in the biotransformation of xenobiotics. The majority of xenobiotics are metabolized in the liver, in which the...
Cytochromes P450 are major metabolic enzymes involved in the biotransformation of xenobiotics. The majority of xenobiotics are metabolized in the liver, in which the highest levels of cytochromes P450 are expressed. Flavonoids are natural compounds to which humans are exposed through everyday diet. In the previous study, selected flavonoid aglycones showed inhibition of CYP3A4 enzyme. Thus, the objective of this study was to determine if these flavonoids inhibit metabolic activity of CYP1A2, CYP2A6, CYP2C8, and CYP2D6 enzymes. For this purpose, the -deethylation reaction of phenacetin was used for monitoring CYP1A2 enzyme activity, coumarin 7-hydroxylation for CYP2A6 enzyme activity, 6-α-hydroxylation of paclitaxel for CYP2C8 enzyme activity, and dextromethorphan -demethylation for CYP2D6 enzyme activity. The generated metabolites were monitored by high-performance liquid chromatography coupled with diode array detection. Hesperetin, pinocembrin, chrysin, isorhamnetin, and morin inhibited CYP1A2 activity; apigenin, tangeretin, galangin, and isorhamnetin inhibited CYP2A6 activity; and chrysin, chrysin-dimethylether, and galangin inhibited CYP2C8. None of the analyzed flavonoids showed inhibition of CYP2D6. The flavonoids in this study were mainly reversible inhibitors of CYP1A2 and CYP2A6, while the inhibition of CYP2C8 was of mixed type (reversible and irreversible). The most prominent reversible inhibitor of CYP1A2 was chrysin, and this was confirmed by the docking study.
Topics: Cytochrome P-450 Enzyme System; Flavonoids; Humans; Molecular Docking Simulation; Substrate Specificity
PubMed: 31480528
DOI: 10.3390/molecules24173174 -
Tanaffos Jan 2019This is a retrospective study to investigate the effects of Carboxyhemoglobin (COHb) and Methemoglobin (MetHb) levels in the diagnosis and prognosis of Pulmonary...
BACKGROUND
This is a retrospective study to investigate the effects of Carboxyhemoglobin (COHb) and Methemoglobin (MetHb) levels in the diagnosis and prognosis of Pulmonary Thromboembolism (PTE).
MATERIALS AND METHODS
Cases that were confirmed with PTE diagnosis using CT Pulmonary Angiography (CTPA) or Ventilation/Perfusion Scintigraphy were accepted as pulmonary embolism. And patients which were excluded using the same methods were accepted as the control group. Patients with carbon monoxide poisoning, Chronic Obstructive Pulmonary Disease (COPD), sepsis, pneumonia, asthma, idiopathic pulmonary fibrosis, bronchiectasis, decompensated cardiac failure or those who used drugs that cause methemoglobinemia (sulphanomides, dapson, phenacetin, primacine, benzocaine) were not included in the study.
RESULTS
In our study, 462 patients were examined with an initial PTE diagnosis. Among these patients, 107 patients who met the inclusion criteria were included in the study. The mean age of all patients was 56.44 ±17.3 years (21-86) and the mean age of patients with PTE diagnosis was 55.3 years and the mean age of excluded patients was 59 years (p:0.27). When the blood gas parameters of both groups were compared, COHb levels in the groups with PTE diagnosis were statistically significantly higher (p=0.001), and the PO levels in the group excluded for PTE diagnosis were statistically significantly higher (p=0.028). In our study, six of our patients (8.1%) died in the early stages because of PTE.
CONCLUSION
In our study, COHb level was found to be statistically significant in the group with PTE. However, this value was not higher than the normal COHb level in the blood. We found that MetHb and COHb levels were not statistically significant in the prognosis of PTE.
PubMed: 31423137
DOI: No ID Found -
Trends in Psychiatry and Psychotherapy Jul 2019Brazil is the world's biggest consumer of crack cocaine, and dependence is a major public health issue. This is the first study to investigate the prevalence of...
INTRODUCTION
Brazil is the world's biggest consumer of crack cocaine, and dependence is a major public health issue. This is the first study to investigate the prevalence of potentially harmful adulterants present in hair samples from Brazilian patients with crack cocaine dependence.
METHOD
We evaluated adulterants in hair samples extracted by convenience from 100 patients admitted at the 48 hour-observation unit of Centro de Referência de Álcool, Tabaco e Outras Drogas (CRATOD), Brazil's largest center for addiction treatment. A cross-sectional analysis was performed with the data obtained.
RESULTS
Adulterants were found in 97% of the analyzed hair samples. The most prevalent adulterant was lidocaine (92%), followed by phenacetin (69%) and levamisole (31%).
CONCLUSION
Adulterants were widely prevalent in hair samples from crack users treated at CRATOD: at least one adulterant was present in virtually all the hair samples collected. This points to a need to monitor adverse effects in the clinical setting in order to provide this high-risk group of patients with prompt and effective care related to the acute and chronic complications associated with these adulterants.
Topics: Adolescent; Adult; Brazil; Cocaine-Related Disorders; Crack Cocaine; Drug Contamination; Female; Hair; Humans; Levamisole; Lidocaine; Male; Phenacetin; Young Adult
PubMed: 31314858
DOI: 10.1590/2237-6089-2017-0143 -
Scientific Reports Jun 2019Over the past two decades, the pig has gained attention as a potential model for human drug metabolism. Cytochrome P450 enzymes (CYP450), a superfamily of... (Comparative Study)
Comparative Study
Over the past two decades, the pig has gained attention as a potential model for human drug metabolism. Cytochrome P450 enzymes (CYP450), a superfamily of biotransformation enzymes, are pivotal in drug metabolism. Porcine CYP450 has been demonstrated to convert typical substrates of human CYP450. Nevertheless, knowledge and insight into porcine CYP450 quantity and substrate selectivity is scant, especially regarding intestinal CYP450. The current study aimed to map the quantities of hepatic and intestinal CYP450 in the conventional pig by using a proteomic approach. Moreover, the selectivity of the six most common used probe substrates (phenacetin, coumarin, midazolam, tolbutamide, dextromethorphan, and chlorzoxazone) for drug metabolizing enzyme subfamilies (CYP1A, CYP2A, CYP3A, CYP2C, CYP2D and CYP2E respectively), was investigated. Hepatic relative quantities were 4% (CYP1A), 31% (CYP2A), 14% (CYP3A), 10% (CYP2C), 28% (CYP2D) and 13% (CYP2E), whereas for the intestine only duodenal CYP450 could be determined with 88% for CYP3A and 12% for CYP2C. Furthermore, the results indicate that coumarin (CYP2A), midazolam (CYP3A), tolbutamide (CYP2C), and dextromethorphan (CYP2D) are as selective for porcine as for human CYP450. However, phenacetin (CYP1A2) and chlorzoxazone (CYP2E1) are less selective for the specific enzyme, despite similarities in selectivity towards the different enzymes involved compared to humans.
Topics: Animals; Cytochrome P-450 Enzyme System; Humans; Inactivation, Metabolic; Intestines; Liver; Pharmaceutical Preparations; Proteomics; Sequence Homology, Amino Acid; Species Specificity; Substrate Specificity; Swine
PubMed: 31239454
DOI: 10.1038/s41598-019-45212-0 -
Scientific Reports Jun 2019Dynamic and reciprocal interactions generated by the communication between tumor cells and their matrix microenvironment, play a major role in the progression of a...
Dynamic and reciprocal interactions generated by the communication between tumor cells and their matrix microenvironment, play a major role in the progression of a tumor. Indeed, the adhesion of specific sites to matrix components, associated with the repeated and coordinated formation of membrane protrusions, allow tumor cells to move along a determined pathway. Our study analyzed the mechanism of action of low-diluted Phenacetinum on murine cutaneous melanoma process in a fibronectin matrix environment. We demonstrated a reduction of dispersed cell migration, early and for as long as 24 h, by altering the formation of cell protrusions. Moreover, low-diluted Phenacetinum decreased cell stiffness highly on peripheral areas, due to a disruption of actin filaments located just under the plasma membrane. Finally, it modified the structure of the plasma membrane by accumulating large ordered lipid domains and disrupted B16 cell migration by a likely shift in the balance between ordered and disordered lipid phases. Whereas the correlation between the excess of lipid raft and cytoskeleton disrupting is not as yet established, it is clear that low-diluted Phenacetinum acts on the actin cytoskeleton organization, as confirmed by a decrease of cell stiffness affecting ultimately the establishment of an effective migration process.
Topics: Animals; Biomechanical Phenomena; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Polarity; Dose-Response Relationship, Drug; Melanoma; Mice; Phenacetin; Skin Neoplasms; Melanoma, Cutaneous Malignant
PubMed: 31235855
DOI: 10.1038/s41598-019-45578-1 -
Iranian Journal of Basic Medical... Mar 2019In this study, a cocktail of probe drugs was used to assess whether lentinan could influence the activities of rat enzymes CYP3A4, CYP2D6, CYP1A2, CYP2C19, and CYP2C9 in...
OBJECTIVES
In this study, a cocktail of probe drugs was used to assess whether lentinan could influence the activities of rat enzymes CYP3A4, CYP2D6, CYP1A2, CYP2C19, and CYP2C9 in vivo.
MATERIALS AND METHODS
Fourteen days after intraperitoneal injection of lentinan, rats were given an oral dose of a cocktail solution containing phenacetin, tolbutamide, omeprazole, metoprolol, and midazolam. Then, we obtained blood in specific durations for the determination of plasma concentration of the probe drugs using UPLC-MS/MS. We also evaluated the pharmacokinetic parameters using the DAS 2.0 software.
RESULTS
We found that various concentrations of lentinan increased the activity of rat CYP1A2, CYP3A4, CYP2D6, and CYP2C19 but not CYP2C9.
CONCLUSION
These findings suggest that clinical application of lentinan combination with CYP3A4, CYP1A2, CYP2C19, or CYP2D6 should be given careful consideration as this may lead to herb-drug interactions and hence treatment failure.
PubMed: 31156791
DOI: 10.22038/ijbms.2019.31611.7611 -
Metabolites Apr 2019Cytochrome P450 1A2 (CYP1A2) is one of the major CYP450 enzymes (CYPs) in the liver, and participates in the biotransformation of various xenobiotics and endogenous...
Cytochrome P450 1A2 (CYP1A2) is one of the major CYP450 enzymes (CYPs) in the liver, and participates in the biotransformation of various xenobiotics and endogenous signaling molecules. The expression and activity of CYP1A2 show large individual differences, due to genetic and environmental factors. In order to discover non-invasive serum biomarkers associated with hepatic CYP1A2, mass spectrometry-based, untargeted metabolomics were first conducted, in order to dissect the metabolic differences in the serum and liver between control rats and β-naphthoflavone (an inducer of CYP1A2)-treated rats. Real-time reverse transcription polymerase chain reaction and pharmacokinetic analysis of phenacetin and paracetamol were performed, in order to determine the changes of mRNA levels and activity of CYP1A2 in these two groups, respectively. Branched-chain amino acids phenylalanine and tyrosine were ultimately focalized, as they were detected in both the serum and liver with the same trends. These findings were further confirmed by absolute quantification via a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based targeted metabolomics approach. Furthermore, the ratio of phenylalanine to tyrosine concentration was also found to be highly correlated with CYP1A2 activity and gene expression. This study demonstrates that metabolomics can be a potentially useful tool for biomarker discovery associated with CYPs. Our findings contribute to explaining interindividual variations in CYP1A2-mediated drug metabolism.
PubMed: 31003543
DOI: 10.3390/metabo9040077