A single variant sequencing method for sensitive and quantitative detection of HIV-1 minority variants.

Sci Rep. 2020 05 18;10(1):8185

Authors: Sidhu G, Schuster L, Liu L, Tamashiro R, Li E, Langaee T, Wagner R, Wang GP

Abstract
HIV drug resistance is a major threat to achieving long-term viral suppression in HIV-positive individuals. Drug resistant HIV variants, including minority variants, can compromise response to antiretroviral therapy. Many studies have investigated the clinical relevance of drug resistant minority variants, but the level at which minority variants become clinically relevant remains unclear. A combination of Primer-ID and deep sequencing is a promising approach that may quantify minority variants more accurately compared to standard deep sequencing. However, most studies that used the Primer-ID method have analyzed clinical samples directly. Thus, its sensitivity and quantitative accuracy have not been adequately validated using known controls. Here, we constructed defined proportions of artificial RNA and virus quasispecies and measured their relative proportions using the Primer-ID based, quantitative single-variant sequencing (qSVS) assay. Our results showed that minority variants present at 1% of quasispecies were detected reproducibly with minimal variations between technical replicates. In addition, the measured frequencies were comparable to the expected frequencies. These data validate the accuracy and reproducibility of the qSVS assay in quantifying authentic HIV minority variants, and support the use of this approach to examine the impacts of minority HIV variants on virologic response and clinical outcome.

PMID: 32424187 [PubMed - indexed for MEDLINE]

Correlation between pharmacokinetics and pharmacogenetics of Selective Serotonin Reuptake Inhibitors and Selective Serotonin and Noradrenaline Reuptake Inhibitors and maternal and neonatal outcomes: Results from a naturalistic study in patients with affective disorders.

Hum Psychopharmacol. 2020 Nov 30;:e2772

Authors: Colombo A, Giordano F, Giorgetti F, Di Bernardo I, Bosi MF, Varinelli A, Cafaro R, Pileri P, Cetin I, Clementi E, Viganò CA, Dell'Osso B

Abstract
OBJECTIVE: Some studies have linked the use of selective serotonin reuptake inhibitors and selective serotonin and noradrenaline reuptake inhibitors (SSRIs/SNRIs) to the risk of perinatal complications. This study explored the relationship between pharmacokinetics and pharmacogenetics, SSRIs/SNRIs tolerability and effectiveness and maternal and newborn outcomes.
METHODS: Fifty-five pregnant women with Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) diagnoses of affective disorders, treated with SSRIs/SNRIs, were recruited and, during the third trimester, their blood samples were collected for pharmacokinetic and pharmacogenetic analyses. Plasma levels and metabolic phenotypes were then related to different obstetrical and maternal outcomes.
RESULTS: The pharmacokinetic data were more stable for Sertraline, Citalopram, and Escitalopram compared to other molecules (p = 0.009). The occurrence of postnatal adaptation syndrome onset was associated with higher plasma levels for Sertraline (median at delivery: 16.7 vs. 10.5 ng/ml), but not for fluoxetine and venlafaxine. Finally, the subgroup within range plasma concentrations had less blood loss than the below range subgroup (p = 0.030).
CONCLUSIONS: Plasma levels of Sertraline, Citalopram and Escitalopram were more frequently in range in late pregnancy when compared to other drugs. Drug plasma concentrations do not strictly correlate with worse perinatal outcomes, but with possible differences between the different drugs.

PMID: 33253437 [PubMed - as supplied by publisher]

Drug response in association with pharmacogenomics and pharmacomicrobiomics: towards a better personalized medicine.

Brief Bioinform. 2020 Dec 01;:

Authors: Hassan R, Allali I, Agamah FE, Elsheikh SSM, Thomford NE, Dandara C, Chimusa ER

Abstract
Researchers have long been presented with the challenge imposed by the role of genetic heterogeneity in drug response. For many years, Pharmacogenomics and pharmacomicrobiomics has been investigating the influence of an individual's genetic background to drug response and disposition. More recently, the human gut microbiome has proven to play a crucial role in the way patients respond to different therapeutic drugs and it has been shown that by understanding the composition of the human microbiome, we can improve the drug efficacy and effectively identify drug targets. However, our knowledge on the effect of host genetics on specific gut microbes related to variation in drug metabolizing enzymes, the drug remains limited and therefore limits the application of joint host-microbiome genome-wide association studies. In this paper, we provide a historical overview of the complex interactions between the host, human microbiome and drugs. While discussing applications, challenges and opportunities of these studies, we draw attention to the critical need for inclusion of diverse populations and the development of an innovative and combined pharmacogenomics and pharmacomicrobiomics approach, that may provide an important basis in personalized medicine.

PMID: 33253350 [PubMed - as supplied by publisher]

Barriers, solutions, and effect of using pharmacogenomics data to support opioid prescribing.

J Manag Care Spec Pharm. 2020 Dec;26(12):1597-1602

Authors: Bright D, Petry N, Roath E, Reckow E, Chavour S

Abstract
Opioid use and misuse are continued issues facing clinicians across all aspects of health care. As clinicians struggle to effectively manage opioid prescribing, pharmacogenomics (PGx) further offers the prescriber an improved ability to understand the potential for an individual patient's genetics to influence opioid efficacy and safety. When PGx data are available at the point of initial prescribing, clinicians can apply that data to drug therapy selection. However, barriers continue to exist relative to PGx data sharing and interpretation, which have created difficulties for widespread PGx implementation. This article briefly describes potential barriers to PGx data integration, strategies to overcome those barriers, and the potential positive effect of successful data sharing on opioid prescribing. Prescription drug monitoring programs (PDMPs) have been successfully operationalized to share controlled substance prescribing data across health care settings. Such data sharing enables clinicians to, among other things, better understand risks associated with misuse. Because a relatively limited volume of PGx data is currently pertinent to opioid prescribing, such PGx data could be added to PDMPs as a way to communicate genetic information within current technology platforms. Not only would this integrate into existing clinical workflow models where PDMP data are accessed at this point of prescribing and/or dispensing, but associated clinical guidance for PGx data interpretation in the context of opioids could be integrated into the workflow process. Such clinical decision support could be provided directly through the PDMP interface for uniformity or could be provided via systems that access PDMP data. Clinical, economic, and policy implications of the inclusion of PGx data within PDMPs are also discussed. Through harnessing PDMP for data sharing, multiple barriers to PGx implementation could be mitigated, and clinicians may have better access to PGx data to optimize opioid prescribing. DISCLOSURES: No outside funding supported this study. Bright has a patent pending related to opioid use disorder risk assessment that includes genetic information and was a collaborator on funded research projects with pharmacogenomics-related companies. Petry has been a consultant to the North Dakota Department of Health and has received grants from IGNITE I and IGNITE II (NIH), unrelated to this work. The other authors are aware of no financial conflicts of interest.

PMID: 33252002 [PubMed - in process]

Association analysis in a Latin American population revealed ethnic differences in rheumatoid arthritis-associated SNPs in Caucasian and Asian populations.

Sci Rep. 2020 05 12;10(1):7879

Authors: Castro-Santos P, Verdugo RA, Alonso-Arias R, Gutiérrez MA, Suazo J, Aguillón JC, Olloquequi J, Pinochet C, Lucia A, Quiñones LA, Díaz-Peña R

Abstract
Large genome-wide association studies (GWAS) have increased our knowledge of the genetic risk factors of rheumatoid arthritis (RA). However, little is known about genetic susceptibility in populations with a large admixture of Amerindian ancestry. The aim of the present study was to test the generalizability of previously reported RA loci in a Latin American (LA) population with admixed ancestry. We selected 128 single nucleotide polymorphisms (SNPs) in linkage equilibrium, with high association to RA in multiple populations of non-Amerindian origin. Genotyping of 118 SNPs was performed in 313 RA patients/487 healthy control subjects by mid-density arrays of polymerase chain reaction (PCR). Some of the identified associations were validated in an additional cohort (250 cases/290 controls). One marker, the SNP rs2451258, located upstream of T Cell Activation RhoGTPase Activating Protein (TAGAP) gene, showed significant association with RA (p = 5 × 10-3), whereas 18 markers exhibited suggestive associations (p < 0.05). Haplotype testing showed association of some groups of adjacent SNPs around the signal transducer and activator of transcription 4 (STAT4) gene (p = 9.82 × 10-3 to 2.04 × 10-3) with RA. Our major finding was little replication of previously reported genetic associations with RA. These results suggest that performing GWAS and admixture mapping in LA populations has the potential to reveal novel loci associated with RA. This in turn might help to gain insight into the 'pathogenomics' of this disease and to explore trans-population differences for RA in general.

PMID: 32398702 [PubMed - indexed for MEDLINE]

Genome-wide analyses disclose the distinctive HLA architecture and the pharmacogenetic landscape of the Somali population.

Sci Rep. 2020 03 27;10(1):5652

Authors: Ali AA, Aalto M, Jonasson J, Osman A

Abstract
African populations are underrepresented in medical genomics studies. For the Somali population, there is virtually no information on genomic markers with significance to precision medicine. Here, we analyzed nearly 900,000 genomic markers in samples collected from 95 unrelated individuals in the North Eastern Somalia. ADMIXTURE program for estimation of individual ancestries revealed a homogenous Somali population. Principal component analysis with PLINK software showed approximately 60% East African and 40% West Eurasian genes in the Somali population, with a close relation to the Cushitic and Semitic speaking Ethiopian populations. We report the unique features of human leukocyte antigens (HLA) in the Somali population, which seem to differentiate from all other neighboring regions compared. Current study identified high prevalence of the diabetes type 1 (T1D) predisposing HLA DR-DQ haplotypes in Somalia. This finding may explain the increased T1D risk observed among Somali children. In addition, ethnic Somalis were found to host the highest frequencies observed thus far for several pharmacogenetic variants, including UGT1A4*2. In conclusion, we report that the Somali population displays genetic traits of significance to health and disease. The Somali dataset is publicly available and will add more information to the few genomic datasets available for African populations.

PMID: 32221414 [PubMed - indexed for MEDLINE]

Variability of voriconazole concentrations in patients with hematopoietic stem cell transplantation and hematological malignancies: influence of loading dose, procalcitonin, and pregnane X receptor polymorphisms.

Eur J Clin Pharmacol. 2020 Apr;76(4):515-523

Authors: Zeng G, Wang L, Shi L, Li H, Zhu M, Luo J, Zhang Z

Abstract
AIMS: Voriconazole (VCZ) displays highly variable pharmacokinetics affecting treatment efficacy and safety. We aimed to identify the factors affecting VCZ steady-state trough concentration (Cssmin) to provide evidence for optimizing VCZ treatment regimens.
METHODS: A total of 510 Cssmin of 172 patients with hematopoietic stem cell transplantation and hematologic malignancies and their clinical characteristics and genotypes of FMO, POR, and PXR were included in this study.
RESULTS: In univariate analysis, the standard loading dose of VCZ significantly increased the Cssmin of VCZ (P < 0.001). The Cssmin of VCZ was significantly correlated with patients' total bilirubin (TB) (P < 0.001) and procalcitonin (PCT) (P < 0.001). FMO3 rs2266780 (P = 0.025), POR rs10954732 (P = 0.015), PXR rs2461817 (P = 0.010), PXR rs7643645 (P = 0.003), PXR rs3732359 (P = 0.014), PXR rs3814057 (P = 0.005), and PXR rs6785049 (P = 0.013) have a significant effect on Cssmin of VCZ. Loading dose, TB, PCT level, and PXRrs3814057 polymorphism were independent influencing factors of VCZ Cssmin in the analysis of multivariate linear regression. And loading dose, PCT, and PXR rs3814057 had significant effects on the probability of the therapeutic window of VCZ.
CONCLUSION: The high variability of VCZ Cssmin may be partially explained by loading dose, liver function, inflammation, and PXR polymorphisms. This study suggests the VCZ standard loading dose regimen significantly increased Cssmin and probability of the therapeutic window providing treatment benefits. Patients in the high PCT group may be more likely to exceed 5.5 μg/mL, thus suffering from VCZ toxicity.

PMID: 31932875 [PubMed - indexed for MEDLINE]

Downregulation of DUSP6, a negative regulator of oncogenic ERK signaling, by ACA-28 induces apoptosis in NIH/3T3 cells overexpressing HER2/ErbB2.

Genes Cells. 2020 Nov 29;:

Authors: Kanda Y, Mizuno A, Takasaki T, Satoh R, Hagihara K, Masuko T, Endo Y, Tanabe G, Sugiura R

Abstract
Dual-specificity phosphatase 6 (DUSP6) is a key negative feedback regulator of the member of the RAS-ERK MAPK signaling pathway that is associated with cellular proliferation and differentiation. Deterioration of DUSP6 expression could therefore result in deregulated growth activity. We have previously discovered ACA-28, a novel anti-cancer compound with a unique property to stimulate ERK phosphorylation and induce apoptosis in ERK-active melanoma cells. However, the mechanism of cancer cell-specific-apoptosis by ACA-28 remains obscure. Here, we investigated the involvement of DUSP6 in the mechanisms of the ACA-28-mediated apoptosis by using the NIH/3T3 cells overexpressing HER2/ErbB2 (A4-15 cells), as A4-15 exhibited higher ERK phosphorylation and are more susceptible to ACA-28 than NIH/3T3. We showed that A4-15 exhibited high DUSP6 protein levels, which require ERK activation. Notably, the silencing of the DUDSP6 gene by siRNA inhibited proliferation and induced apoptosis in A4-15, but not in NIH/3T3, indicating that A4-15 requires high DUSP6 expression for growth. Importantly, ACA-28 preferentially downregulated the DUSP6 protein and proliferation in A4-15 via the proteasome, whilst it stimulated ERK phosphorylation. Collectively, the upregulation of DUSP6 may exert a growth-promoting role in cancer cells overexpressing HER2. DUSP6 downregulation in ERK-active cancer cells might have the potential as a novel cancer measure.

PMID: 33249692 [PubMed - as supplied by publisher]

Identification and functional study of genetic polymorphisms in cyclic nucleotide phosphodiesterase 3A (PDE3A).

Ann Hum Genet. 2020 Nov 28;:

Authors: Kim YR, Yi M, Cho SA, Kim WY, Min J, Shin JG, Lee SJ

Abstract
Phosphodiesterase 3A (PDE3A) is an enzyme that plays an important role in the regulation of cyclic adenosine monophosphate (cAMP)-mediated intracellular signaling in cardiac myocytes and platelets. PDE3A hydrolyzes cAMP, which results in a decrease in intracellular cAMP levels and leads to platelet activation. Whole-exome sequencing of 50 DNA samples from a healthy Korean population revealed a total of 13 single nucleotide polymorphisms including five missense variants, D12N, Y497C, H504Q, C707R, and A980V. Recombinant proteins for the five variants of PDE3A (and wild-type protein) were expressed in a FreeStyle 293 expression system with site-directed mutagenesis. The expression of the recombinant PDE3A proteins was confirmed with Western blotting. Catalytic activity of the PDE3A missense variants and wild-type enzyme was measured with a PDE-based assay. Effects of the missense variants on the inhibition of PDE3A activity by cilostazol were also investigated. All variant proteins showed reduced activity (33-53%; p < .0001) compared to the wild-type protein. In addition, PDE3A activity was inhibited by cilostazol in a dose-dependent manner and was further suppressed in the missense variants. Specifically, the PDE3A Y497C showed significantly reduced activity, consistent with the predictions of in silico analyses. The present study provides evidence that individuals carrying the PDE3A Y497C variant may have lower enzyme activity for cAMP hydrolysis, which could cause interindividual variation in cAMP-mediated physiological functions.

PMID: 33249558 [PubMed - as supplied by publisher]

ABCB1 c.2677G>T/c.3435C>T diplotype increases the early-phase oral absorption of losartan.

Arch Pharm Res. 2020 Nov 29;:

Authors: Shin HB, Jung EH, Kang P, Lim CW, Oh KY, Cho CK, Lee YJ, Choi CI, Jang CG, Lee SY, Bae JW

Abstract
Losartan has been shown to be a substrate of the drug-efflux transporter MDR1, encoded by the ABCB1 gene. ABCB1 c.2677G>T and c.3435C>T variants are known to be associated with reduced expression and function of P-glycoprotein (P-gp). We investigated the effects of ABCB1 diplotype on the pharmacokinetics of losartan. Thirty-eight healthy Korean volunteers with different ABCB1 diplotypes [c.2677G> T and c.3435C>T; carriers of GG/CC (n = 13), GT/CT (n = 12) and TT/TT (n = 13) diplotype] were recruited and administered a single 50 mg oral dose of losartan potassium. Losartan and its active metabolite E-3174 samples in plasma and urine were collected up to 10 and 8 h after drug administration, respectively, and the concentrations of both samples were determined by HPLC method. Significant differences were observed in Cmax of losartan and losartan plus E-3174 (Lo + E) among the three diplotype groups (both P < 0.01). However, the power of the performed test is less than the desired power (0.800). The tmax of losartan and E-3174 in three diplotype groups were also significantly different (both P < 0.01). The AUC values of Lo + E were significantly different among the three diplotype groups until 6 h after losartan administration (P < 0.01). On the contrary, AUC at the periods of 8-10 h and 10 h-infinity of Lo + E were significantly lower in the TT/TT group than in the GG/CC group. Urinary excretion of losartan until 4 h after losartan administration in the TT/TT group was higher than that of the GG/CC group. These results suggest that c.2677G>T/c.3435C>T diplotypes of ABCB1 may significantly increase the early-phase absorption of losartan, but not the total absorption.

PMID: 33249530 [PubMed - as supplied by publisher]

As-needed anti-inflammatory reliever therapy for asthma management: evidence and practical considerations.

Clin Exp Allergy. 2020 Nov 28;:

Authors: Bianco A, Contoli M, Di Marco F, Saverio Mennini F, Papi A, participants of the regional meetings

Abstract
Asthma is a chronic respiratory disease in which airway inflammation is a key feature, even in the milder expressions of the disease. The conventional pharmacological approach to mild asthma has long relied on reliever therapy with as-needed short-acting beta-agonists (SABA), while anti-inflammatory maintenance with inhaled corticosteroids (ICS) has been reserved for patients with more persistent asthma. Poor adherence to maintenance treatment is an important issue in asthma management, and can partly explain suboptimal symptom control. Over-reliance on SABA bronchodilators for rapid symptom relief is common in real life and potentially leads to an increased risk of asthma morbidity and mortality. Combined anti-inflammatory and reliever medications in a single inhaler have the potential to overcome these limitations. Recent studies in patients with mild asthma have shown that anti-inflammatory reliever therapy with budesonide-formoterol, given on an as-needed basis, is superior to SABA in ensuring asthma control, and non-inferior to budesonide maintenance therapy in preventing exacerbations. To address the implications of these important findings for the management of patients with asthma, Italian specialists convened at a series of meetings held during the second half of 2018 across Italy. This article presents their position on these topics, and includes a review of the evidence supporting the use of anti-inflammatory reliever therapy in mild asthma and the implementation of this novel approach in clinical practice.

PMID: 33247470 [PubMed - as supplied by publisher]

Fifteen-minute consultation: Vulval soreness in the prepubertal girl.

Arch Dis Child Educ Pract Ed. 2020 Nov 27;:

Authors: Chanchlani N, Hodes D

PMID: 33246924 [PubMed - as supplied by publisher]

CYP2C19 Loss-of-Function is Associated with Increased Risk of Ischemic Stroke after Transient Ischemic Attack in Intracranial Atherosclerotic Disease.

J Stroke Cerebrovasc Dis. 2020 Nov 24;30(2):105464

Authors: Patel PD, Vimalathas P, Niu X, Shannon CN, Denny JC, Peterson JF, Chitale RV, Fusco MR

Abstract
OBJECTIVES: Intracranial atherosclerotic disease (ICAD) is responsible for 8-10% of acute ischemic strokes, and resistance to antiplatelet therapy is prevalent. CYP2C19 gene loss-of-function (up to 45% of patients) causes clopidogrel resistance. For patients with asymptomatic ICAD and ICAD characterized by transient ischemic attack (TIA), this study measures the effect of CYP2C19 loss-of-function on ischemic stroke risk during clopidogrel therapy.
MATERIALS AND METHODS: From a deidentified database of medical records, patients were selected with ICD-9/10 code for ICAD, availability of CYP2C19 genotype, clopidogrel exposure, and established patient care. Dual-antiplatelet therapy patients were included. Patients with prior ischemic stroke, other neurovascular condition, intracranial angioplasty/stenting, or observation time <1 month were excluded. Time-to-event analysis using Cox regression was conducted to model first-time ischemic stroke events based on CYP2C19 loss-of-function allele and adjusted for age, gender, race, length of aspirin, length of concurrent antiplatelet/anticoagulant treatment, diabetes, coagulopathy, hypertension, heart disease, atrial fibrillation, and lipid disorder. Subset analyses were performed for asymptomatic and post-TIA subtypes of ICAD.
RESULTS: A total of 337 patients were included (median age 68, 58% male, 88% Caucasian, 26% CYP2C19 loss-of-function). A total of 161 (47.8%) patients had TIA at time of ICAD diagnosis, while 176 (52.2%) were asymptomatic. First-time ischemic stroke was observed among 20 (12.4%) post-TIA ICAD patients and 17 (9.7%) asymptomatic ICAD patients. Median observation time was 2.82 [IQR 1.13-5.17] years. CYP2C19 loss-of-function allele was associated with ischemic stroke event (HR 2.2, 95% CI 1.1-4.3, p=0.020) after adjustment. Post-TIA ICAD patients had a higher risk of ischemic stroke from CYP2C19 loss-of-function (HR 3.4, 95% CI 1.4-8.2, p=0.006).
CONCLUSIONS: CYP2C19 loss-of-function was associated with 3-fold increased risk of first-time ischemic stroke for ICAD patients treated with clopidogrel after TIA. This effect was not observed for asymptomatic ICAD. CYP2C19-guided antiplatelet selection may improve stroke prevention in ICAD after TIA.

PMID: 33246208 [PubMed - as supplied by publisher]

Immune-related gene data-based molecular subtyping related to the prognosis of breast cancer patients.

Breast Cancer. 2020 Nov 27;:

Authors: Mu G, Ji H, He H, Wang H

Abstract
BACKGROUND: Breast cancer (BC), which is the most common malignant tumor in females, is associated with increasing morbidity and mortality. Effective treatments include surgery, chemotherapy, radiotherapy, endocrinotherapy and molecular-targeted therapy. With the development of molecular biology, immunology and pharmacogenomics, an increasing amount of evidence has shown that the infiltration of immune cells into the tumor microenvironment, coupled with the immune phenotype of tumor cells, will significantly affect tumor development and malignancy. Consequently, immunotherapy has become a promising treatment for BC prevention and as a modality that can influence patient prognosis.
METHODS: In this study, samples collected from The Cancer Genome Atlas (TCGA) and ImmPort databases were analyzed to investigate specific immune-related genes that affect the prognosis of BC patients. In all, 64 immune-related genes related to prognosis were screened, and the 17 most representative genes were finally selected to establish the prognostic prediction model of BC (the RiskScore model) using the Lasso and StepAIC methods. By establishing a training set and a test set, the efficiency, accuracy and stability of the model in predicting and classifying the prognosis of patients were evaluated. Finally, the 17 immune-related genes were functionally annotated, and GO and KEGG signal pathway enrichment analyses were performed.
RESULTS: We found that these 17 genes were enriched in numerous BC- and immune microenvironment-related pathways. The relationship between the RiskScore and the clinical characteristics of the sample and signaling pathways was also analyzed.
CONCLUSIONS: Our findings indicate that the prognostic prediction model based on the expression profiles of 17 immune-related genes has demonstrated high predictive accuracy and stability in identifying immune features, which can guide clinicians in the diagnosis and prognostic prediction of BC patients with different immunophenotypes.

PMID: 33245478 [PubMed - as supplied by publisher]

The Future of Analytical and Interpretative Toxicology: Where are We Going and How Do We Get There?

J Anal Toxicol. 2020 Nov 27;:

Authors: Wille SMR, Elliott S

Abstract
(Forensic) toxicology has faced many challenges, both analytically and interpretatively, especially in relation to an increase in potential drugs of interest. Analytical toxicology and its application to medicine and forensic science have progressed rapidly within the past centuries. Technological innovations have enabled detection of more substances with increasing sensitivity in a variety of matrices. Our understanding of the effects (both intended and unintended) have also increased along with determination and degree of toxicity. However, it is clear there is even more to understand and consider. The analytical focus has been on typical matrices such as blood and urine but other matrices could further increase our understanding, especially in postmortem (PM) situations. Within this context, the role of PM changes and potential redistribution of drugs requires further research and identification of markers of its occurrence and extent. Whilst instrumentation has improved, in the future, nanotechnology may play a role in selective and sensitive analysis as well as bioassays. Toxicologists often only have an advisory impact on pre-analytical and pre-interpretative considerations. The collection of appropriate samples at the right time in an appropriate way as well as obtaining sufficient circumstance background is paramount in ensuring an effective analytical strategy to provide useful results that can be interpreted within context. Nevertheless, key interpretative considerations such as pharmacogenomics and drug-drug interactions as well as determination of tolerance remain and in the future, analytical confirmation of an individual's metabolic profile may support a personalized medicine and judicial approach. This should be supported by the compilation and appropriate application of drug data pursuant to the situation. Specifically, in PM circumstances, data pertaining to where a drug was not/may have been/was contributory will be beneficial with associated pathological considerations. This article describes the challenges faced within toxicology and discusses progress to a future where they are being addressed.

PMID: 33245325 [PubMed - as supplied by publisher]

Changes in Telepsychiatry Regulations during the COVID-19 Pandemic: 17 Countries and Regions' Approaches to an Evolving Healthcare Landscape.

Psychol Med. 2020 Nov 27;:1-33

Authors: Kinoshita S, Cortright K, Crawford A, Mizuno Y, Yoshida K, Hilty D, Guinart D, Torous J, Correll CU, Castle DJ, Rocha D, Yang Y, Xiang YT, Kølbæk P, Dines D, ElShami M, Jain P, Kallivayalil R, Solmi M, Favaro A, Veronese N, Seedat S, Shin S, de Pablo GS, Chang CH, Su KP, Karas H, Kane JM, Yellowlees P, Kishimoto T

PMID: 33243311 [PubMed - as supplied by publisher]

Effect of CYP3A5*3 genotypes on lumefantrine plasma concentrations among malaria-HIV-infected women.

Pharmacogenomics. 2020 Nov 27;:

Authors: Adegbola AJ, Soyinka JO, Bolaji OO

Abstract
Aim: We aimed to assess the effect of a functional polymorphism of CYP3A5 on lumefantrine pharmacokinetics. Patients & methods: Sixty-nine women diagnosed with malaria received standard doses of artemether-lumefantrine. Concentration-time data for lumefantrine and genotyping data were obtained for each participant. Pharmacokinetic-genotype associative relationships were assessed using linear regressions, Mann-Whitney U-test or Kruskal-Wallis statistics. Results: Average age and weight (standard deviation) of the patients were 33 (6.8) years and 59.5 (11.6) kg, respectively. CYP3A5*3 genotype associated with the log-transformed maximum concentration with the median (interquartile range) values of 8279 (6516-13,420) and 6331 (4093-8631) ng/ml (p = 0.032) among the carriers and noncarriers of CYP3A5*3, respectively. Besides, the NR1I3 c.152-1089T>C genotypes had an associative trend with the lumefantrine area under the curve (AUC0-96h) and clearance. Conclusion: CYP3A5*3 genetic variant is associated with a high maximum plasma concentration of lumefantrine. This warrants further investigations on the association between CYP3A5*3 gene variants, lumefantrine pharmacokinetics and electrophysiological effect.

PMID: 33243092 [PubMed - as supplied by publisher]

Assessing COVID-19 susceptibility through analysis of the genetic and epigenetic diversity of ACE2 mediated SARS-CoV-2 entry.

Pharmacogenomics. 2020 Nov 27;:

Authors: Ragia G, Manolopoulos VG

Abstract
There is considerable variation in disease course among individuals infected with SARS-CoV-2. Many of them do not exhibit any symptoms, while some others proceed to develop COVID-19; however, severity of COVID-19 symptoms greatly differs among individuals. Focusing on the early events related to SARS-CoV-2 entry to cells through the ACE2 pathway, we describe how variability in (epi)genetic factors can conceivably explain variability in disease course. We specifically focus on variations in ACE2, TMPRSS2 and FURIN genes, as central components for SARS-CoV-2 infection, and on other molecules that modulate their expression such as CALM, ADAM-17, AR and ESRs. We propose a genetic classifier for predicting SARS-CoV-2 infectivity potential as a preliminary tool for identifying the at-risk-population. This tool can serve as a dynamic scaffold being updated and adapted to validated (epi)genetic data. Overall, the proposed approach holds potential for better personalization of COVID-19 handling.

PMID: 33243086 [PubMed - as supplied by publisher]

Inhibitory Effects of Raw-Extract Centella asiatica (RECA) on Acetylcholinesterase, Inflammations, and Oxidative Stress Activities via In Vitro and In Vivo.

Molecules. 2020 Feb 17;25(4):

Authors: Hafiz ZZ, Amin M'M, Johari James RM, Teh LK, Salleh MZ, Adenan MI

Abstract
Centella asiatica (C. asiatica) is one of the medicinal plants that has been reported to exert comprehensive neuroprotection in vitro and in vivo. In view of this, the present study was performed to investigate the effect of ethanolic extract of C. asiatica, designated as raw-extract of C. asiatica (RECA) in reducing the acetylcholinesterase (AChE), inflammations, and oxidative stress activities via both in vitro (SH-SY5Y and RAW 264.7 cells) and in vivo (Sprague Dawley rats). Quantitative high-performance liquid chromatography analysis reveals that RECA contains a significantly high proportion of glycosides than the aglycones with madecassoside as the highest component, followed by asiaticoside. Treatment of SH-SY5Y cells with RECA significantly reduced the AChE activity in a concentration-dependent manner with an IC50 value of 31.09 ± 10.07 µg/mL. Furthermore, the anti-inflammatory and antioxidant effects of RECA were evaluated by lipopolysaccharides (LPS)-stimulated RAW 264.7 cells. Our results elucidated that treatment with RECA significantly suppressed the level of pro-inflammatory cytokine/mediators and oxidative stress released in a concentration-dependent manner. Interestingly, these patterns of inhibition were consistent as observed in the LPS-induced neuroinflammation Sprague Dawley rats' model. The highest concentration used in the two models presented the most significant results. Herein, our findings strongly suggest that RECA may offer therapeutic potential for the treatment of Alzheimer's disease through inhibiting the AChE, inflammation, and oxidative stress activities.

PMID: 32079355 [PubMed - indexed for MEDLINE]

A Comparative Analysis of Cytochrome P450 Activities in Paired Liver and Small Intestinal Samples from Patients with Obesity.

Drug Metab Dispos. 2020 01;48(1):8-17

Authors: Krogstad V, Peric A, Robertsen I, Kringen MK, Wegler C, Angeles PC, Hjelmesæth J, Karlsson C, Andersson S, Artursson P, Åsberg A, Andersson TB, Christensen H

Abstract
The liver and small intestine restrict oral bioavailability of drugs and constitute the main sites of pharmacokinetic drug-drug interactions. Hence, detailed data on hepatic and intestinal activities of drug metabolizing enzymes is important for modeling drug disposition and optimizing pharmacotherapy in different patient populations. The aim of this study was to determine the activities of seven cytochrome P450 (P450) enzymes in paired liver and small intestinal samples from patients with obesity. Biopsies were obtained from 20 patients who underwent Roux-en-Y gastric bypass surgery following a 3-week low-energy diet. Individual hepatic and intestinal microsomes were prepared and specific probe substrates in combined incubations were used for determination of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A activities. The activities of CYP2C8, CYP2C9, CYP2D6, and CYP3A were quantified in both human liver microsomes (HLM) and human intestinal microsomes (HIM), while the activities of CYP1A2, CYP2B6, and CYP2C19 were only quantifiable in HLM. Considerable interindividual variability was present in both HLM (9- to 23-fold) and HIM (5- to 55-fold). The median metabolic HLM/HIM ratios varied from 1.5 for CYP3A to 252 for CYP2C8. The activities of CYP2C9 in paired HLM and HIM were positively correlated (r = 0.74, P < 0.001), while no interorgan correlations were found for activities of CYP2C8, CYP2D6, and CYP3A (P > 0.05). Small intestinal CYP3A activities were higher in females compared with males (P < 0.05). Hepatic CYP2B6 activity correlated negatively with body mass index (r = -0.72, P < 0.001). These data may be useful for further in vitro-in vivo predictions of drug disposition in patients with obesity. SIGNIFICANCE STATEMENT: Hepatic and intestinal drug metabolism is the key determinant of oral drug bioavailability. In this study, paired liver and jejunum samples were obtained from 20 patients with obesity undergoing gastric bypass surgery following a 3-week low-energy diet. We determined the hepatic and small intestinal activities of clinically important P450 enzymes and provide detailed enzyme kinetic data relevant for predicting in vivo disposition of P450 substrates in this patient population.

PMID: 31685482 [PubMed - indexed for MEDLINE]