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AMIA ... Annual Symposium Proceedings.... 2022: Polypharmacy can be a source of adverse drug events including those caused by drug to drug interaction (DDI) exposures. Web-based DDI databases are available to...
: Polypharmacy can be a source of adverse drug events including those caused by drug to drug interaction (DDI) exposures. Web-based DDI databases are available to researchers for the identification of potential DDI exposures. Rather than relying on potentially incomplete DDI databases, large clinical data repositories (CDR) which are integrated data sources fed with millions of heterogeneous electronic health records (EHRs) containing real-world data should be leveraged for data driven DDI identification. : To explore and validate the viability of clinical data repositories as data driven resources for clinically important adverse drug events detection and surveillance. : This work leverages a minimum clinical data set from the University of Minnesota's CDR to identify drugs that have statin to drug interaction (SDI) potential and compares the findings with results of web based DDI databases. Using an SDI identification matrix, we identified several potential novel SDI drugs that were not mentioned in the web-based sources but explored through our study as drugs with SDI potential. : Drugs flagged by our SDI identification matrix but not mentioned in the web-based sources include Lysine, Ketotifen, Latanoprost, Methylcellulose, Oxazepam, Linseed Oil, and others. : Our findings identified potential gaps regarding the completeness, currency, and overall reliability of open source and commercial DDI databases. CDRs can be a primary source for identifying drug to drug interactions. : clinical data repository, drug to drug interaction databases, drug to drug interaction, statin to drug interaction, polypharmacy, statin to drug interaction identification matrix, adverse drug event, statin.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Reproducibility of Results; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Risk Assessment
PubMed: 37128384
DOI: No ID Found -
Talanta Aug 2023Benzodiazepines can make victims more docile, they are frequently used in drug-facilitated crimes, such as robberies and sexual assaults. Therefore, it is essential to...
Benzodiazepines can make victims more docile, they are frequently used in drug-facilitated crimes, such as robberies and sexual assaults. Therefore, it is essential to develop techniques for determining whether these chemicals are present in relation with illegal activity is crucial. Therefore, to determine the presence of five benzodiazepines (alprazolam, clonazepam, diazepam, lorazepam, and oxazepam) in water, alcoholic beverages, and non-alcoholic beverages, a simple and direct, miniaturized, and effective vortex assisted ultrasound based microextraction using solidification of floating organic droplets (VAUS-ME-SFO) in combination with LC-MS/MS was developed. 1-Undecanol and acetonitrile, respectively, served as the extractant and disperser solvents. Many other parameters affect the efficiency of the developed analytical procedure VAUS-ME-SFO/LC-MS/MS. These parameters were optimized using Plackett Burman Design and Central Composite Design to obtain reliable results. The optimum conditions for the extraction were: 10.0 mL of sample; 180 μL acetonitrile, as a dispersive solvent; 200 μL of 1-undecanol, as an extraction solvent; pH 7; 105 s of vortex agitation; 120 s of ultrasonication application and 3 min of centrifugation at 7000 rpm. The benzodiazepines were separated by a chromatographic separation technique carried out by a UPLC system consisting of a binary mobile phase. The solvent system comprises of 0.1% Formic acid in Milli-Q (Solvent A) and 0.1% Formic acid in ACN (Solvent B) with a gradient flow of 3.5 min total analysis time. Under the optimized conditions, the calibration curve was studied in the range of 0.124-7.810 ng mL. The regression correlation coefficient (R) value of all targeted analytes ranges from 0.993 to 0.999. The LOD and LOQ of VAUS-ME-SFO methods using LC-MS/MS analysis range from 0.316 to 0.968 ng mL and 1.055-3.277 ng mL respectively. The repeatability within a day varied from 0.6 to 3.5%, and the reproducibility across days varied from 2.2 to 6.3%. The recoveries ranges for water, alcoholic and non-alcoholic beverages from 70.77 to 114.53%, 63.20-102.21% and 66.23-113.28% respectively. Further, the degradation kinetics was studied to establish the half-life of each targeted analyte in the matrix undertaken in the study. The water samples were classified based on their BDZs residues. This implies that the more health care and anthropogenic activity, the more the BDZs residue will be in water samples.
Topics: Benzodiazepines; Chromatography, Liquid; Water; Reproducibility of Results; Tandem Mass Spectrometry; Solvents; Beverages; Liquid Phase Microextraction
PubMed: 37121139
DOI: 10.1016/j.talanta.2023.124572 -
Current Drug Metabolism 2023Benzodiazepines (BZDs) are compounds that contain one diazepine ring and two benzene rings, and are widely used to treat central nervous system diseases. However, drug...
BACKGROUND
Benzodiazepines (BZDs) are compounds that contain one diazepine ring and two benzene rings, and are widely used to treat central nervous system diseases. However, drug abuse and BZDs' illegal addition may affect normal life and even lead to grave social harm. As BZDs may be metabolized and eliminated quickly, it is of great theoretical and practical significance to clarify their metabolic profile.
OBJECTIVE
In this paper, LC-Q-TOF/MS-based fragmentation behavior has been investigated for nine benzodiazepine drugs available and widely used in clinical treatment (diazepam, nitrazepam, clonazepam, oxazepam, lorazepam, alprazolam, estazolam, triazolam, and midazolam), and their metabolic profile has been studied by using in vitro human liver microsomal incubation.
METHODS
A regular human liver microsomal system was used to investigate the potential biotransformation of the nine benzodiazepines in vitro, and an LC-Q/TOF-MS was used to perform fragmentation behavior studies and metabolite identification.
RESULTS
As a result, characteristic fragmentation pathway and diagnostic fragment ions of the nine BZDs were analyzed, and 19 metabolites of the 9 benzodiazepines were found and identified, with glucuronidation and hydroxylation considered as their most important metabolic pathways.
CONCLUSION
These experimental data add to our knowledge of the nine benzodiazepine drugs and their metabolism study, which could provide useful information and evidence of their in vivo metabolic profile prediction and help promote their monitoring in both clinical use and social/illegal abuse.
Topics: Humans; Benzodiazepines; Midazolam; Mass Spectrometry; Chromatography, Liquid
PubMed: 37114779
DOI: 10.2174/1389200224666230419090733 -
Chemical & Pharmaceutical Bulletin 2023The degradation behavior of three benzodiazepines (BZPs)-lormetazepam (LMZ), lorazepam, and oxazepam-with hydroxy groups on the diazepine ring in artificial gastric...
The degradation behavior of three benzodiazepines (BZPs)-lormetazepam (LMZ), lorazepam, and oxazepam-with hydroxy groups on the diazepine ring in artificial gastric juice and the effect of storage pH conditions on drug degradability were monitored using an LC/photodiode array detector (PDA) to estimate their pharmacokinetics in the stomach. Although the three BZPs degraded in artificial gastric juice, none could be restored, despite increasing the storage pH, implying that the degradation reaction was irreversible. As for LMZ, we discussed the physicochemical parameters, such as the activation energy and activation entropy involved in the degradation reaction as well as the reaction kinetics; one of the degradation products was isolated and purified for structural analysis. In the LMZ degradation experiment, peaks corresponding to degradation products, (A) and (B), were detected through the LC/PDA measurements. Regarding the degradation behavior, we hypothesized that LMZ was degraded into (B) via (A), where (A) was an intermediate and (B) was the final product. Although the isolation of degradation product (A) was challenging, degradation product (B) could be isolated and was confirmed to be "methanone, [5-chloro-2-(methylamino)phenyl](2-chlorophenyl)-" based on structure determination using various instrumental analyses. The compound exhibited axis asymmetry as determined using single-crystal X-ray structure analysis. Because the formation of degradation product (B) was irreversible, it would be prudent to target the final degradation product (B) and LMZ for identification when detecting LMZ in human stomach contents, such as during forensic dissection.
Topics: Humans; Benzodiazepines; Gastric Juice; Stomach; Kinetics
PubMed: 37005255
DOI: 10.1248/cpb.c22-00911 -
The Science of the Total Environment May 2023For the first time, several pharmaceuticals have been defined as priority substances in the new proposal of the revision of the Water Framework Directive (WFD)....
For the first time, several pharmaceuticals have been defined as priority substances in the new proposal of the revision of the Water Framework Directive (WFD). Consequently, environmental quality standards have been determined for several drugs. This is the case with the antiepileptic carbamazepine, which is considered as hazardous in healthcare settings by The National Institute for Occupational Safety and Health (NIOSH). This organism considers as such drugs that have shown teratogenicity, carcinogenicity, genotoxicity or other developmental, reproductive, or organ toxicity at low doses in studies with animals or humans. This study has been focused on the non-carcinogenic drugs classified in group 2, and their presence in the environment. This group contains many different therapeutic agents such as antineoplastics, psychoactive drugs, immunosuppressants and antivirals, among others. Of the 116 drugs included in the list, 26 have been found in aquatic environmental matrices. Certain drugs have received most attention (e.g., the antiepileptic carbamazepine, progesterone and the antidepressant paroxetine) while others completely lack environmental monitoring. Carbamazepine, fluconazole, paroxetine and warfarin have been found in invertebrates' tissues, whereas carbamazepine, oxazepam and paroxetine have been found in fish tissues. The main aim of the NIOSH's hazardous drug list is to inform healthcare professionals about adequate protection measures to prevent occupational exposure to these pharmaceuticals. However, this list contains useful information for other professionals and researchers such as environmental scientists. The paucity of relevant environmental data of certain hazardous pharmaceuticals might be important to help in the prioritization of compounds that may demand further research.
Topics: Animals; United States; Humans; Anticonvulsants; Paroxetine; National Institute for Occupational Safety and Health, U.S.; Environment; Water Pollutants, Chemical; Pharmaceutical Preparations; Carbamazepine; Hazardous Substances
PubMed: 36822426
DOI: 10.1016/j.scitotenv.2023.162280 -
Biochimica Et Biophysica Acta. Proteins... May 2023UDP-glucuronosyltransferase 2B15 (UGT2B15) is a crucial phase II drug-metabolizing enzyme, which glucuronidates various compounds, including clinical drugs and hormones....
UDP-glucuronosyltransferase 2B15 (UGT2B15) is a crucial phase II drug-metabolizing enzyme, which glucuronidates various compounds, including clinical drugs and hormones. Mutants might affect glucuronidation, leading to a disruption of drug metabolism in vivo and decrease of therapeutic effect. Here, we mainly analyzed two representative mutants, H401P and L446S, on UGT2B15 activity using glucuronidation assays, molecular dynamic (MD) simulation and X-ray diffraction methods. The enzyme activity of L446S obviously increased six-fold than the wild type, although the enzyme activities of P191L, T374A, and H401P were lost apparently. Furthermore, we used MD simulations to calculate the energy change in the catalytic process of H401P and L446S, and the results indicated the free binding energies of H401P mutant to oxazepam and UDPGA were -30.98 ± 1.00 kcal/mol and -36.42 ± 1.04 kcal/mol, respectively, increased obviously compared to wild type, suggesting the mutation on position 401 had a crucial effect on the catalysis. Moreover, the three-dimensional structure of UGT2B15 C-terminal domain L446S was determined through protein crystallography and X-ray diffraction technology and the results suggested that one more hydrogen bonding between S446 and K410 was formed in the S446 crystal structure, compared to the wild type. Isothermal titration calorimetry assay further revealed the K values of C-terminal domain of UGT2B15 harbored L446S towards the cofactor UDPGA was similar to the value of wild type. Above all, our results pointed out that H401P and L446S affected the enzyme activity by different mechanism. Our work provided a helpful mechanism for variance explained in the UGTs catalyzation process.
Topics: Glucuronosyltransferase; Uridine Diphosphate Glucuronic Acid; X-Ray Diffraction; Kinetics
PubMed: 36610584
DOI: 10.1016/j.bbapap.2023.140888 -
Toxics Dec 2022Stimulants belonging to the amphetamine group nowadays pose an undeniable worldwide threat to the life and health of users. Intoxications of domestic animals also occur,...
Stimulants belonging to the amphetamine group nowadays pose an undeniable worldwide threat to the life and health of users. Intoxications of domestic animals also occur, which can either be accidental or related to intentional human action. This study presents the first ever reported case of a simultaneous amphetamine and methamphetamine intoxication of a cat, along with the results of toxicological studies. Blood, urine, vitreous humor and liver were collected during the cat's autopsy and analyzed by UHPLC─QqQ─MS/MS. The sample preparation technique was based on one-step precipitation of proteins with cold acetonitrile. The determined amphetamine concentrations in the collected biological materials were 93.4 ng/mL in blood, 496.6 ng/mL in urine, 589.2 ng/mL in the vitreous humor and 291.2 ng/g in liver, respectively. Methamphetamine concentrations were 45.5 ng/mL in blood, 263.1 ng/mL in urine, 351.2 ng/mL in vitreous humor, and 97.7 ng/g in liver. Other substances were also found in the biological material, i.e., diazepam, oxazepam and nordiazepam. Cases of intentional or accidental poisoning of pets with psychoactive substances are a serious problem, carrying the risk to the health and life of the animal. Therefore, it is important to increase awareness of the high risk of poisoning of domestic animals, as well as to learn about the incompletely understood mechanisms of pharmacokinetics of various drugs in animals, including cats.
PubMed: 36548582
DOI: 10.3390/toxics10120749 -
Journal of Analytical Toxicology Mar 2023Benzodiazepines and z-hypnotics are detected in the majority of fatal overdose cases in Norway, often in combination with other drugs of abuse, and their concentrations...
Benzodiazepines and z-hypnotics are detected in the majority of fatal overdose cases in Norway, often in combination with other drugs of abuse, and their concentrations in peripheral blood (PB) might be important to elucidate the cause of death. In some forensic autopsies, PB is however not available. The aim of the present study was to compare concentrations of benzodiazepines and z-hypnotics in five alternative matrices to assess whether these concentrations are comparable to concentrations in PB. A total of 109 forensic autopsy cases were included. PB, cardiac blood (CB), pericardial fluid (PF), psoas muscle (PM), lateral vastus muscle (LVM) and vitreous humor (VH) from each case were analyzed using ultra high performance liquid chromatography--tandem mass spectrometry. We were able to detect clonazepam, 7-aminoclonazepam, flunitrazepam, 7-aminoflunitrazepam, nitrazepam, 7-aminonitrazepam, diazepam, nordiazepam, oxazepam, alprazolam, midazolam, zopiclone and zolpidem in all the analyzed matrices. Concentrations measured in VH were generally much lower than those of PB for all compounds except zopiclone. 7-Amino metabolite concentrations were high compared to the parent compounds, although less so for the muscle samples. Concentrations of the parent nitrobenzodiazepines in muscles were higher than those in PB, but for the other compounds, concentrations in muscle showed good correspondence with PB. Both CB and PF were viable alternative matrices for PB, although a larger variation and a tendency for higher concentrations in PF were observed. This study shows that CB, PM, LVM and PF can give comparable concentrations to PB for benzodiazepines and z-hypnotics, while VH was less suitable. The concentrations in alternative matrices must, however, be interpreted carefully.
Topics: Benzodiazepines; Hypnotics and Sedatives; Autopsy; Azabicyclo Compounds
PubMed: 36542823
DOI: 10.1093/jat/bkac106 -
Deutsches Arzteblatt International Jan 2023The term potentially inadequate medication (PIM) is used to describe substances that may be unsuitable for use inthe elderly and should be avoided. The PRISCUS list,...
BACKGROUND
The term potentially inadequate medication (PIM) is used to describe substances that may be unsuitable for use inthe elderly and should be avoided. The PRISCUS list, published in 2010, was the first catalog of PIM designed for the Germandrug market to become adopted in practice. While 24% of German patients aged ≥ 65 years were prescribed at least one PIMper year in 2009, the proportion in 2019 was only 14.5%.
METHODS
In a three-round Delphi process, experts from clinical practice and research evaluated whether selected substancesare PIM for the elderly. The participants were provided with dedicated literature including systematic reviews carried out for theparticular purposes of this project.
RESULTS
Fifty-nine persons took part in the Delphi process and, in addition, contributed comments and therapeutic alternatives.Altogether, 187 substances were classed as PIM. One hundred thirty-three of the substances now listed were not in the originalPRISCUS list: these include some oral antidiabetics, all of the selective COX-2 inhibitors, and moderately long acting benzodiazepinessuch as oxazepam. For some other substances, e.g., proton pump inhibitors (PPI), the advisability of treatment formore than 8 weeks was considered as potentially inappropriate, as was the use of ibuprofen in doses >1200 mg/day and formore than 1 week without PPI. Risperidone for more than 6 weeks is also PIM.
CONCLUSION
The new, greatly extended PRISCUS list must now be validated in epidemiological and prospective studies and itspracticability in routine daily use must be verified.
Topics: Aged; Humans; Prospective Studies; Hypoglycemic Agents; Ibuprofen; Proton Pump Inhibitors
PubMed: 36507719
DOI: 10.3238/arztebl.m2022.0377 -
Biosensors Oct 2022Despite all the psychological advantages of alprazolam, its long list of toxic properties and interactions has caused concern and highlighted the need for a reliable...
Despite all the psychological advantages of alprazolam, its long list of toxic properties and interactions has caused concern and highlighted the need for a reliable sensing method. In this study, we developed a simple, highly sensitive electrochemical nanobiosensor to determine the desirable dose of alprazolam, averting the undesirable consequences of overdose. Gold nanourchins (AuNUs) and iron-nickel reduced graphene oxide (Fe-Ni@rGO) were immobilized on a glassy carbon electrode, which was treated beforehand. The electrode surface was characterized using cyclic voltammetry, Fourier transform infrared spectroscopy, scanning electron microscopy/energy-dispersive X-ray spectroscopy, and differential pulse voltammetry. The fabricated sensor showed two linear ranges (4 to 500 µg L and 1 to 50 mg L), low limit of detection (1 µg L), high sensitivity, good repeatability, and good recovery. Increased -OH and carboxyl (-COOH) groups on the electrode surface, resulting in improved the adsorption of alprazolam and thus lower limit of detection. This nanobiosensor could detect alprazolam powder dissolved in diluted blood serum; we also studied other benzodiazepine drugs (clonazepam, oxazepam, and diazepam) with this nanobiosensor, and results were sensible, with a significant difference.
Topics: Alprazolam; Graphite; Nanocomposites; Gold; Electrodes; Electrochemical Techniques
PubMed: 36354454
DOI: 10.3390/bios12110945