scholarly journals CYP2D6 Reduced Function Variants and Genotype/Phenotype Translations of CYP2D6 Intermediate Metabolizers: Implications for Personalized Drug Dosing in Psychiatry

2021 ◽  
Vol 12 ◽  
Author(s):  
Espen Molden ◽  
Marin M. Jukić
Keyword(s):  
Functional Score ◽  
Individual Dose ◽  
Dose Individualization ◽  
Drug Dosing ◽  
Long Time ◽  
Ultrarapid Metabolizer ◽  
Variant Alleles ◽  
International Experts ◽  
Current Guidelines ◽  
Intermediate Metabolizers

Genetic differences in cytochrome P450 (CYP)-mediated metabolism have been known for several decades. The clinically most important polymorphic CYP enzyme is CYP2D6, which plays a key role in the metabolism of many antidepressants and antipsychotics, along with a range of non-psychiatric medications. Dose individualization based on CYP2D6 genotype to improve the effect and safety of drug treatment has been an ambition for a long time. Clinical use of CYP2D6 genotyping is steadily increasing; however, for pre-emptive genotyping to be successful in predicting individual dose requirements, high precision of genotype-to-phenotype translations are required. Recently, guidelines for assigning CYP2D6 enzyme activity scores of CYP2D6 variant alleles, and subsequent diplotype-to-phenotype translations, were published by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group. Consensus on assigning activity scores of CYP2D6 variant alleles and translating diplotype scores into CYP2D6 poor, intermediate, normal, or ultrarapid metabolizer groups were obtained by consulting 37 international experts. While assigning enzyme activities of non-functional (score 0) and fully functional (score 1) alleles are straightforward, reduced function variant alleles are more complex. In this article, we present data showing that the assigned activity scores of reduced function variant alleles in current guidelines are not of sufficient precision; especially not for CYP2D6*41, where the guideline activity score is 0.5 compared to 0.05–0.15 in pharmacogenetic studies. Due to these discrepancies, CYP2D6 genotypes with similar guidelinediplotype scores exhibit substantial differences in CYP2D6 metabolizer phenotypes. Thus, it is important that the guidelines are updated to be valid in predicting individual dose requirements of psychiatric drugs and others metabolized by CYP2D6.

scholarly journals Allele-Specific Change of Concentration and Functional Gene Dose for the Prediction of Steady-State Serum Concentrations of Amitriptyline and Nortriptyline in CYP2C19 and CYP2D6 Extensive and Intermediate Metabolizers

2004 ◽  
Vol 50 (9) ◽  
pp. 1623-1633 ◽  
Author(s):  
Werner Steimer ◽  
Konstanze Zöpf ◽  
Silvia von Amelunxen ◽  
Herbert Pfeiffer ◽  
Julia Bachofer ◽  
...  
Keyword(s):  
Functional Gene ◽  
Extensive Metabolizers ◽  
Specific Change ◽  
Gene Dose ◽  
Drug Concentrations ◽  
Steady State Serum ◽  
Ultrarapid Metabolizer ◽  
Allele Specific ◽  
Few Data ◽  
Intermediate Metabolizers

Abstract Background: Recently, new polymorphisms were described in connection with intermediate and ultrarapid CYP2D6 metabolism. These may allow a much desired prediction of metabolic activity within the extensive metabolizer group. The functional consequences are still being discussed with few data available for clinical patients. Methods: We conducted a prospective, blinded two-center study seeking correlations between CYP2C19 (*2,*3, and *4; conventional PCR) and CYP2D6 genotypes (*1 to *10, *35, and *41; real-time and multiplex PCR) and drug concentrations (Emit® and HPLC) in 50 Caucasians receiving amitriptyline (AT; 75 mg twice a day). Results: Eighteen CYP2C19 heterozygotes (*1/*2) had higher AT (P = 0.033) and lower nortriptyline (NT; P = 0.059) concentrations than 30 homozygotes (*1/*1). For CYP2D6, we calculated two new indices, i.e., the allele-specific change of concentration on identical background (ASCOC) and a quantitative functional gene dose. The ASCOC describes the change in NT concentration attributable to a mutant allele compared with the wild type. We found significantly higher concentrations for alleles *4 (95.6%; P <0.0001), *10 (63.3%; P <0.001), and *41 (39.8%; P <0.0001) but not for *2 and *35. Assigning of semiquantitative gene doses of 0, 0.5, or 1 to each allele instead of applying the current classification system (predicted phenotypes: 3 intermediate metabolizers, 46 extensive metabolizers, and 1 ultrarapid metabolizer) produced significant NT concentration differences: gene doses of 0.5 (n =3), 1 (n = 14), 1.5 (n = 11), 2 (n = 21) and 3 (n = 1; P <0.00001). Conclusions: AT and NT concentrations can be predicted within the group of CYP2D6 extensive metabolizers. The ASCOC provides substantial advantages compared with current methods of analysis. CYP2D6 but not CYP2C19 correlates with the sum of both concentrations used to guide AT therapy.

Deactivation of weapons from the perspective of European Union and Kosovo

2016 ◽  
Vol 8 (1) ◽  
pp. 123-136
Author(s):  
Paweł Suchanek
Keyword(s):  
Member States ◽  
Eu Member States ◽  
Technical Requirements ◽  
Post Conflict ◽  
Domestic Legislation ◽  
Legitimate Concern ◽  
Long Time ◽  
Set Up ◽  
International Experts ◽  
Common Understanding

Despite existing regulations on weapon acquisition, possession, trade, transfer over the border on EU and UN level, for a long time an issue of deactivation had not been addressed by EU in a comprehensive way until December 2015, the aftermath of the series of terrorist attacks in several EU Member States. . For some years after the amended Firearms Directive 2008/15/EC had come into force, except for the framework guidelines, there was neither a sense of common understanding for the concept of deactivation, nor definite, technical requirements for all EU Member States. In result, deactivated firearms that were legally transferred or illegally trafficked within EU territory were very likely to be reactivated by criminals and re-introduced into illicit weapon market. The article describes the path that has finally led to the establishment of the EU requirements on deactivation, presenting on the other hand, the struggle for the set-up of sound anti-reactivation provisions by one of the newest countries on the European map, that is Kosovo. This young state has had to overcome the post conflict situation and has started to introduce a versatile control over the civilian weapon market. As Kosovo has been strictly cooperating with EU and UN on public security related issues, the topic of regulating the weapon market became one of the issues of legitimate concern both for Brussels and Pristina. In case of the deactivation, Kosovo authorities assisted by international experts, prepared comprehensive solutions in their domestic legislation, which came into force long before the establishment of EU common guidelines on deactivation standards and techniques for ensuring that deactivated firearms are rendered irreversibly inoperable set in December 2015.

scholarly journals Carboxymethylcellulose/MOF-5/Graphene oxide bio-nanocomposite as antibacterial drug nanocarrier agent

Bioimpacts ◽  
2018 ◽  
Vol 9 (1) ◽  
pp. 5-13 ◽  
Author(s):  
Zahra Karimzadeh ◽  
Siamak Javanbakht ◽  
Hassan Namazi
Keyword(s):  
Drug Delivery ◽  
Antibacterial Activity ◽  
Graphene Oxide ◽  
Metal Organic Framework ◽  
Antibacterial Drug ◽  
Drug Dosing ◽  
Solvothermal Technique ◽  
Analysis Methods ◽  
Long Time ◽  
Stomach Ph

Introduction: In recent years, more attention was dedicated to developing new methods for designing of drug delivery systems. The aim of present work is to improve the efficiency of the antibacterial drug delivery process, and to realize and to control accurately the release. Methods: First, graphene oxide (GO) was prepared according to the modified Hummers method then the GO was modified with carboxymethylcellulose (CMC) and Zn-based metal-organic framework (MOF-5) through the solvothermal technique. Results: Performing the various analysis methods including scanning electron microscope (SEM), X-ray diffraction (XRD), EDX, Fourier transform infrared (FTIR) spectroscopy and Zeta potentials on the obtained bio-nanocomposite showed that the new modified GO has been prepared. With using common analysis methods the structure of synthesized materials was determined and confirmed and finally, their antibacterial behavior was examined based on the broth microdilution methods. Conclusion: Carboxymethylcellulose/MOF-5/GO bio-nanocomposite (CMC/MOF-5/GO) was successfully synthesized through the solvothermal technique. Tetracycline (TC) was encapsulated in the GO and CMC/MOF-5/GO. The drug release tests showed that the TC-loaded CMC/MOF5/GO has an effective protection against stomach pH. With controlling the TC release in the gastrointestinal tract conditions, the long-time stability of drug dosing was enhanced. Furthermore, antibacterial activity tests showed that the TC-loaded CMC/MOF-5/GO has an antibacterial activity to negatively charge E. coli bacteria in contrast to TC-loaded GO.

scholarly journals Tamsulosin Associated with Interstitial Lung Damage in CYP2D6 Variant Alleles Carriers

2020 ◽  
Vol 21 (8) ◽  
pp. 2770 ◽  
Author(s):  
Naomi T. Jessurun ◽  
Petal A. Wijnen ◽  
Aalt Bast ◽  
Eugène P. van Puijenbroek ◽  
Otto Bekers ◽  
...  
Keyword(s):  
Poor Metabolizers ◽  
Lung Damage ◽  
Control Group ◽  
Nucleotide Polymorphisms ◽  
Drug Induced ◽  
Single Nucleotide ◽  
Causative Agents ◽  
Variant Alleles ◽  
Intermediate Metabolizers

Drugs are serious but underestimated causative agents of interstitial lung disease (ILD). Both cytotoxic and immune mechanisms may be involved in drug-induced ILD (DI-ILD). We aimed to investigate whether polymorphisms of relevant CYP enzymes involved in the metabolization of tamsulosin might explain the pathologic mechanism of the DI-ILD in the cases with suspected tamsulosin DI-ILD. We collected 22 tamsulosin-associated DI-ILD cases at two ILD Expertise Centers in the Netherlands between 2009 and 2020. CYP2D6, CYP2C9, CYP2C19, CYP3A4, and CYP3A5 single nucleotide polymorphisms were genotyped and compared with a control group of 78 healthy Caucasian male volunteers. Nine cases were phenotyped as CYP2D6 poor metabolizers and 13 as CYP2D6 intermediate metabolizers. The phenotypes of the cases differed significantly from those of the healthy controls, with more poor metabolizers. After withdrawal of tamsulosin, the pulmonary condition of three cases had improved, six patients had stabilized, and one patient stabilized after reducing the tamsulosin dose. The described 22 cases suggest that an association between the presence of CYP2D6 allelic variants and tamsulosin-associated ILD is highly likely. These cases highlight the importance of both clinical and genetic risk stratification aimed to achieve a more accurate prevention of DI-ILD in the future and enhance the quality of life of patients.

200kv superconducting cryo electron microscope

1987 ◽  
Vol 45 ◽  
pp. 642-643
Author(s):  
M. Iwatsuki ◽  
Y. Kokubo ◽  
Y. Harada ◽  
J. Lehman
Keyword(s):  
Electron Microscope ◽  
Structure Analysis ◽  
Organic Materials ◽  
Strong Interactions ◽  
Specimen Preparation ◽  
Great Effort ◽  
Electron Microscopic ◽  
Crystal Fields ◽  
Special Skill ◽  
Long Time

In recent years, the electron microscope has been significantly improved in resolution and we can obtain routinely atomic-level high resolution images without any special skill. With this improvement, the structure analysis of organic materials has become one of the interesting targets in the biological and polymer crystal fields.Up to now, X-ray structure analysis has been mainly used for such materials. With this method, however, great effort and a long time are required for specimen preparation because of the need for larger crystals. This method can analyze average crystal structure but is insufficient for interpreting it on the atomic or molecular level. The electron microscopic method for organic materials has not only the advantage of specimen preparation but also the capability of providing various information from extremely small specimen regions, using strong interactions between electrons and the substance. On the other hand, however, this strong interaction has a big disadvantage in high radiation damage.

A Stationary Solution of High-Energy Electron Reflection (HEER) for An Arbitrary Surface

1990 ◽  
Vol 48 (2) ◽  
pp. 374-375
Author(s):  
YIQUN MA
Keyword(s):  
Stationary Solution ◽  
High Energy ◽  
Bloch Wave ◽  
Dynamical Theory ◽  
High Energy Electron ◽  
Bulk Materials ◽  
Periodic Surface ◽  
Electron Transmission ◽  
Electron Reflection ◽  
Long Time

For a long time, the development of dynamical theory for HEER has been stagnated for several reasons. Although the Bloch wave method is powerful for the understanding of physical insights of electron diffraction, particularly electron transmission diffraction, it is not readily available for the simulation of various surface imperfection in electron reflection diffraction since it is basically a method for bulk materials and perfect surface. When the multislice method due to Cowley & Moodie is used for electron reflection, the “edge effects” stand firmly in the way of reaching a stationary solution for HEER. The multislice method due to Maksym & Beeby is valid only for an 2-D periodic surface.Now, a method for solving stationary solution of HEER for an arbitrary surface is available, which is called the Edge Patching method in Multislice-Only mode (the EPMO method). The analytical basis for this method can be attributed to two important characters of HEER: 1) 2-D dependence of the wave fields and 2) the Picard iteractionlike character of multislice calculation due to Cowley and Moodie in the Bragg case.

Direct imaging of charge transfer

1996 ◽  
Vol 54 ◽  
pp. 680-681
Author(s):  
Yimei Zhu ◽  
J. Tafto
Keyword(s):  
Charge Transfer ◽  
Electron Diffraction ◽  
Scattering Amplitude ◽  
High Temperature Superconductors ◽  
Charge Carriers ◽  
Image Charge ◽  
Net Charge ◽  
Long Time ◽  
Electron Holes ◽  
First Time

The electron holes confined to the CuO2-plane are the charge carriers in high-temperature superconductors, and thus, the distribution of charge plays a key role in determining their superconducting properties. While it has been known for a long time that in principle, electron diffraction at low angles is very sensitive to charge transfer, we, for the first time, show that under a proper TEM imaging condition, it is possible to directly image charge in crystals with a large unit cell. We apply this new way of studying charge distribution to the technologically important Bi2Sr2Ca1Cu2O8+δ superconductors.Charged particles interact with the electrostatic potential, and thus, for small scattering angles, the incident particle sees a nuclei that is screened by the electron cloud. Hence, the scattering amplitude mainly is determined by the net charge of the ion. Comparing with the high Z neutral Bi atom, we note that the scattering amplitude of the hole or an electron is larger at small scattering angles. This is in stark contrast to the displacements which contribute negligibly to the electron diffraction pattern at small angles because of the short g-vectors.

Microstructural characterization of plasma-processed Ti-Al metal matrix composites

1989 ◽  
Vol 47 ◽  
pp. 552-553
Author(s):  
M. G. Burke ◽  
M. N. Gungor ◽  
M. A. Burke
Keyword(s):  
High Temperature ◽  
Titanium Aluminide ◽  
Plasma Processing ◽  
Microstructural Characterization ◽  
High Temperature Strength ◽  
Matrix Composites ◽  
Intermetallic Matrix ◽  
Long Time ◽  
Strength And Stiffness ◽  
Intermetallic Matrix Composites

Intermetallic matrix composites are candidates for ultrahigh temperature service when light weight and high temperature strength and stiffness are required. Recent efforts to produce intermetallic matrix composites have focused on the titanium aluminide (TiAl) system with various ceramic reinforcements. In order to optimize the composition and processing of these composites it is necessary to evaluate the range of structures that can be produced in these materials and to identify the characteristics of the optimum structures. Normally, TiAl materials are difficult to process and, thus, examination of a suitable range of structures would not be feasible. However, plasma processing offers a novel method for producing composites from difficult to process component materials. By melting one or more of the component materials in a plasma and controlling deposition onto a cooled substrate, a range of structures can be produced and the method is highly suited to examining experimental composite systems. Moreover, because plasma processing involves rapid melting and very rapid cooling can be induced in the deposited composite, it is expected that processing method can avoid some of the problems, such as interfacial degradation, that are associated with the relatively long time, high temperature exposures that are induced by conventional processing methods.

Gum arabic helps prepare better lacey polymer films for specimen support in electron microscopy

1993 ◽  
Vol 51 ◽  
pp. 240-241
Author(s):  
Shailesh R. Sheth ◽  
Jayesh R. Bellare
Keyword(s):  
Electron Microscopy ◽  
Polymer Films ◽  
Gum Arabic ◽  
Complete Removal ◽  
Ammonium Bromide ◽  
Release Agent ◽  
Astigmatism Correction ◽  
Long Time ◽  
Micro Holes ◽  
Cetyl Trimethyl Ammonium

Specimen support and astigmatism correction in Electron Microscopy are at least two areas in which lacey polymer films find extensive applications. Although their preparation has been studied for a very long time, present techniques still suffer from incomplete release of the film from its substrate and presence of a large number of pseudo holes in the film. Our method ensures complete removal of the entire lacey film from the substrate and fewer pseudo holes by pre-treating the substrate with Gum Arabic, which acts as a film release agent.The method is based on the classical condensation technique for preparing lacey films which is essentially deposition of minute water or ice droplets on the substrate and laying the polymer film over it, so that micro holes are formed corresponding to the droplets. A microscope glass slide (the substrate) is immersed in 2.0% (w/v) aq. CTAB (cetyl trimethyl ammonium bromide)-0.22% (w/v) aq.

On-line image readout in CTEM

1994 ◽  
Vol 52 ◽  
pp. 400-401
Author(s):  
K.-H. Herrmann ◽  
W. D. Rau ◽  
R. Sikeler
Keyword(s):  
Primary Electron ◽  
Digital Information ◽  
Electron Hole ◽  
Detection Technology ◽  
Long Time ◽  
On Line ◽  
Electron Image ◽  
Optical Transfer ◽  
Detection Quantum Efficiency ◽  
Technical Solutions

Quantitative recording of electron patterns and their rapid conversion into digital information is an outstanding goal which the photoplate fails to solve satisfactorily. For a long time, LLL-TV cameras have been used for EM adjustment but due to their inferior pixel number they were never a real alternative to the photoplate. This situation has changed with the availability of scientific grade slow-scan charged coupled devices (CCD) with pixel numbers exceeding 106, photometric accuracy and, by Peltier cooling, both excellent storage and noise figures previously inaccessible in image detection technology. Again the electron image is converted into a photon image fed to the CCD by some light optical transfer link. Subsequently, some technical solutions are discussed using the detection quantum efficiency (DQE), resolution, pixel number and exposure range as figures of merit.A key quantity is the number of electron-hole pairs released in the CCD sensor by a single primary electron (PE) which can be estimated from the energy deposit ΔE in the scintillator,

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