Effects of CYP2D6 activity on the efficacy and safety of mirtazapine in patients with depressive disorders and comorbid alcohol use disorder

The objective of the study was to investigate the effects of CYP2D6 activity on the efficacy and safety of mirtazapine in patients with depressive disorders and comorbid alcohol use disorder who received mirtazapine. The study included 109 Russian patients who received mirtazapine at a dose of 30.0 [15.0; 45.0] mg per day. Genotyping of CYP2D6*4 (1846G > A, rs3892097) was performed using real-time polymerase chain reaction with allele-specific hybridization. The activity of CYP2D6 was evaluated by determining the concentration of endogenous substrate of the enzyme and its urinary metabolite — pinoline to 6-hydroxy-1,2,3,4-tetrahydro-beta-carboline ratio, using high-performance liquid chromatography – mass spectrometry. The statistically significant differences between the scores on the Hamilton Depression Rating Scale (HAMD) in patients with different genotypes were revealed by day 16: (GG) 5.0 [3.0; 6.0], (GA) 1.5 [1.0; 3.2] (p 0.05). This study demonstrated that an increased CYP2D6 activity reduces the efficacy of treatment with mirtazapine.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Multivariate Statistical Analysis of Surface Enhanced Raman Spectra of Human Serum for Alzheimer’s Disease Diagnosis

Alzheimer’s disease (AD) is the most common form of dementia worldwide and is characterized by progressive cognitive decline. Along with being incurable and lethal, AD is difficult to diagnose with high levels of accuracy. Blood serum from Alzheimer’s disease (AD) patients was analyzed by surface-enhanced Raman spectroscopy (SERS) coupled with multivariate statistical analysis. The obtained spectra were compared with spectra from healthy controls (HC) to develop a simple test for AD detection. Serum spectra from AD patients were further compared to spectra from patients with other neurodegenerative dementias (OD). Colloidal silver nanoparticles (AgNPs) were used as the SERS-active substrates. Classification experiments involving serum SERS spectra using artificial neural networks (ANNs) achieved a diagnostic sensitivity around 96% for differentiating AD samples from HC samples in a binary model and 98% for differentiating AD, HC, and OD samples in a tertiary model. The results from this proof-of-concept study demonstrate the great potential of SERS blood serum analysis to be developed further into a novel clinical assay for the effective and accurate diagnosis of AD

Bis(oxiranes) Containing Cyclooctane Core: Synthesis and Reactivity towards NaN₃

Reactions of oxirane ring opening provide a powerful tool for regio- and stereoselective synthesis of polyfunctional and heterocyclic compounds, widely used in organic chemistry and drug design. Cyclooctane, alongside other medium-sized rings, is of interest as a novel molecular platform for the construction of target-oriented leads. Additionally, cyclooctane derivatives are well known to be prone to transannular reactions, which makes them a promising object in the search for novel approaches to polycyclic structures. In the present work, a series of cyclooctanediones was studied in Corey-Chaykovsky reactions, and novel spirocyclic bis(oxiranes) containing cyclooctane core, namely, 1,5-dioxadispiro[2.0.2.6]dodecane and 1,8-dioxadispiro[2.3.2.3]dodecane, were synthesized. Ring opening of the obtained bis(oxiranes) upon treatment with sodium azide was investigated, and it was found that the reaction path is determined by the reciprocal orientation of oxygen atoms in the oxirane moieties. Diastereomers of the bis(oxiranes) with cis-orientation underwent independent ring opening, supplying corresponding diazidodiols, while in the case of stereoisomers with trans-orientation, domino-like reactions occurred, including intramolecular nucleophilic attack and the formation of a novel three- or six-membered O-containing ring. Summarily, a straightforward approach to polyfunctional compounds containing cyclooctane or oxabicyclo[3.3.1]nonane cores, employing bis(oxiranes), was elaborated

How do CYP2C19*2 and CYP2C19*17 genetic polymorphisms affect the efficacy and safety of diazepam in patients with alcohol withdrawal syndrome?

© 2020 Walter de Gruyter GmbH, Berlin/Boston.Background: Diazepam is one of the most commonly prescribed tranquilizers for therapy of alcohol withdrawal syndrome (AWS). Despite its popularity, there is currently no precise information on the effect of genetic polymorphisms on its efficacy and safety. The objective of our study was to investigate the effect of CYP2C19*2 and CYP2C19*17 genetic polymorphisms on the efficacy and safety of diazepam in patients with AWS. Methods: The study was conducted on 30 Russian male patients suffering from the AWS who received diazepam in injections at a dosage of 30.0 mg/day for 5 days. The efficacy and safety assessment was performed using psychometric scales and scales for assessing the severity of adverse drug reactions. Results: Based on the results of the study, we revealed the differences in the efficacy of therapy in patients with different CYP2C19 681G>A (CYP2C19*2, rs4244285) genotypes: (CYP2C19*1/*1) -8.5 [-15.0; -5.0], (CYP2C19*1/*2 and CYP2C19*2/*2) -12.0 [-13.0; -9.0], p = 0.021. The UKU scale scores, which were used to evaluate the safety of therapy, were also different: (CYP2C19*1/*1) 7.0 [6.0; 12.0], (CYP2C19*1/*2 and CYP2C19*2/*2) 9.5 [8.0; 11.0], p = 0.009. Patients carrying different CYP2C19 -806C>T (CYP2C19*17, rs12248560) genotypes also demonstrated differences in therapy efficacy and safety rates. Conclusions: Thus, the effects of CYP2C19*2 and CYP2C19*17 genetic polymorphisms on the efficacy of diazepam were demonstrated.info:eu-repo/semantics/publishedVersio

Effects of CYP2C19*2 polymorphisms on the efficacy and safety of phenazepam in patients with anxiety disorder and comorbid alcohol use disorder

© 2020 Future Science Group.Introduction: Phenazepam therapy can often be ineffective and some patients develop dose-related adverse drug reactions. Aim. The purpose of this research was to study the effect of the CYP2C19*2 (681G>A, rs4244285) in patients with anxiety disorders and alcohol dependence taking phenazepam therapy. Materials & methods: Patients (175 males, average age: 37.16 ± 7.84 years) received phenazepam in tablet form for 5 days. Genotyping was performed by real-time polymerase chain reaction. Results: The statistically significant differences in the UKU Side-Effect Rating Scale scores on the fifth day of therapy: (CYP2C19*1/*1) 2.00 [1.00; 2.00), (CYP2C19*1/*2) 7.00 (7.00; 7.00), (CYP2C19*2/*2) 9.00 (8.00; 9.00), p < 0.001. Conclusion: This study demonstrated the different efficacy and safety of phenazepam in patients with different genotypes of CYP2C19*2.This work was supported by the project titled “Fundamental research and exploratory research in priority areas of research” of the Russian Science Foundation and by the President’s Grant of state support for the young scientists (project MK-2460.2018.7).info:eu-repo/semantics/publishedVersio

Antimicrobial Effects of Sulfonyl Derivative of 2(5H)-Furanone against Planktonic and Biofilm Associated Methicillin-Resistant and -Susceptible Staphylococcus aureus

The gram-positive opportunistic bacterium Staphylococcus aureus is one of the most common causatives of a variety of diseases including skin and skin structure infection or nosocomial catheter-associated infections. The biofilm formation that is an important virulence factor of this microorganism renders the antibiotic therapy ineffective, because biofilm-embedded bacteria exhibit strongly increased tolerance to antimicrobials. Here, we describe a novel 3-chloro-5(S)-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy]-4-[4-methylphenylsulfonyl]-2(5H)-furanone (F105), possessing a sulfonyl group and l-menthol moiety. Minimal inhibitory and bactericidal concentration values (MIC and MBC) of F105 were 10 and 40 mg/L, respectively, suggesting F105 biocidal properties. F105 exhibits pronounced activity against biofilm-embedded S. aureus and increases the efficacy of aminoglycosides (amikacin, gentamicin, and kanamycin) and benzalkonium chloride with fractional inhibitory concentration index values of 0.33–0.44 and 0.29, respectively, suggesting an alternative external treatment option, e.g., for wound infections. Moreover, low concentrations (0.5–1.3 mg/L) of F105 reduced the MICs of these antimicrobials twofold. By using confocal laser scanning microscopy and CFU counting, we show explicitly that F105 also restores the antimicrobial activity of gentamicin and ampicillin against S. aureus biofilms by several orders of magnitude. Biofilm structures were not destroyed but sterilized, with embedded cells being almost completely killed at twofold MBC. While F105 is quite toxic (CC50/MBC ratio 0.2), our data suggest that the F105 chemotype might be a promising starting point for the development of complex topical agents for combined anti-staphylococcal biofilm-therapies restoring the efficacy of some antibiotics against difficult to treat S. aureus biofilm