LC-MS/MS-Based Quantification of 9 Antiepileptic Drugs From a Dried Sample Spot Device.

Ther Drug Monit. 2019 06;41(3):331-339

Authors: DʼUrso A, Cangemi G, Barco S, Striano P, DʼAvolio A, de Grazia U

Abstract
BACKGROUND: Therapeutic drug monitoring (TDM) of antiepileptic drugs (AEDs) is commonly performed on plasma or serum. The use of dried plasma spots (DPSs) could represent a useful tool to facilitate sample shipment to reference laboratories. In this article, the authors describe the application of a commercially available UHPLC-MS/MS method for the determination of 9 commonly prescribed AEDs (levetiracetam, lacosamide, topiramate, ethosuximide, lamotrigine, rufinamide, zonisamide, primidone, and oxcarbazepine and its active metabolite 10-OH-monohydroxycarbazepine) to DPS collected on dried sample spot devices (DSSDs).
METHOD: Fifty microliters of plasma were spotted on DSSD. After being air-dried at room temperature, they were extracted using an organic extraction solution containing the appropriate deuterated internal standards. The chromatographic separation was performed on a UHPLC reversed-phase C-18 column, and the analytes were quantified using a triple quadrupole mass spectrometer (LC-MS/MS).
RESULTS: The assay was linear over the concentration ranges tested with a total runtime of 10.3 minutes. Recovery ranged from 93.7% to 106.8%. Intraday and interday precision for all quality control levels, including lower limit of quantification, ranged from 2.1% to 18.4% and 2.1% to 13.2%. Intraday and interday accuracy biases ranged from -11.7% to 14.3% and -9.2% to 8.0%. The absence of matrix effects was also tested and confirmed. Real samples derived from patients under therapy were also analyzed, and the comparison of results obtained from DSSD with those obtained from plasma showed that the 2 matrices were interchangeable. Stability tests performed on both quality controls, and real samples demonstrated that DSSDs can be easily stored and shipped at room temperature for 15 days.
CONCLUSIONS: The application of the LC-MS/MS method allowed the authors to obtain a very specific, sensitive, and rapid (total runtime = 10.3 minutes) quantification of 9 AEDs starting from very low volumes of plasma samples. The main advantage of DPS over wet samples is room temperature storage and shipment, which lowers shipment costs and makes it suitable for routine TDM. Moreover, in comparison with other alternative matrices, DPS allows for the use of the same therapeutic ranges on which routine TDM is based. DPS on DSSD can thus be considered as a useful and cheap tool for the broader application of TDM.

PMID: 30688867 [PubMed - in process]

The Current Status of Genes and Genetic Testing in Emergency Medicine: A Narrative Review.

Adv J Emerg Med. 2020;4(1):e10

Authors: Aghamir SMK, Ebrahimi M, Khatami F

Abstract
Context: An emergency is any medical problem that could cause death or permanent injury if not treated quickly. In some occasions, the kind of urgent intervention depends on patient's exact genetic background. Unfortunately, the importance of genes in medical emergencies has been forgotten in recent decades.
Evidence acquisition: In order to find relevant articles, we searched two databases of Pubmed and Embase. The exact words of "genes", "genetics", "epigenetics", "DNA", and "emergency" were used alone and in combination. All studies like randomized clinical trials (RCT), case/controls, case series, case reports, and review articles were studied to find the related data. No time limitation was considered for the studies.
Results: Several aspects of genetic testing are newly considered in emergency departments including cell-free DNA (cfDNA) for disease diagnosis, pharmacogenetics for decreasing the adverse drug effects, and personalized medicine for exact emergency interventions in diseases like Vascular Ehlers-Danlos syndrome (vEDS). Data from genetic testing and genome wide association studies have yielded promising results to make medical emergency interventions more beneficial in the near future.
Conclusion: Taking everything into consideration, several advanced genetic and epigenetic alteration technologies can change emergency medicine for the better. Personalized genetic data of patients can turn emergency medicine to personalized medicine.

PMID: 31938779 [PubMed]

Hematological status and endurance performance predictors after low altitude training supported by normobaric hypoxia: a double-blind, placebo controlled study.

Biol Sport. 2019 Dec;36(4):341-349

Authors: Sitkowski D, Szygula Z, Surała O, Orysiak J, Zdanowicz R, Pokrywka A, Starczewski M, Malczewska-Lenczowska J

Abstract
The benefits of altitude/hypoxic training for sea level performance are still under debate. This study examined the effects of low altitude training supported by normobaric hypoxia on hematological status and endurance performance predictors in elite female cyclists. Twenty-two female cyclists trained for 3 weeks at low altitude (<1100 m) and 2 weeks near sea level. During the first 3 weeks, 15 subjects stayed in hypoxic rooms simulating an altitude of 2200 m (+NH group, n = 8) or 1000 m (placebo group, n = 7), and 7 (control group) stayed in regular rooms. Significant increases in total hemoglobin mass (tHb-mass: p = 0.008, p = 0.025), power at 4 mmol·l-1 lactate (PAT4: p = 0.004, p = 0.005) (in absolute and relative values, respectively) and maximal power (PF: p = 0.034) (in absolute values) were observed. However, these effects were not associated with normobaric hypoxia. Changes in tHb-mass were not associated with initial concentrations of ferritin or transferrin receptor, whereas changes in relative tHb-mass (r = -0.53, p = 0.012), PF (r = -0.53, p = 0.01) and PAT4 (r = -0.65, p = 0.001) were inversely correlated with initial values. Changes in tHb-mass and PAT4 were positively correlated (r = 0.50, p = 0.017; r = 0.47, p = 0.028). Regardless of normobaric hypoxia application, low altitude training followed by sea-level training might improve hematological status in elite female cyclists, especially with relatively low initial values of tHb-mass, which could translate into enhanced endurance performance.

PMID: 31938005 [PubMed]

Genetic Polymorphisms of Pharmacogenes among the Genetically Isolated Circassian Subpopulation from Jordan.

J Pers Med. 2020 Jan 06;10(1):

Authors: Al-Eitan LN, Rababa'h DM, Hakooz NM, Alghamdi MA, Dajani RB

Abstract
Several genetic variants have been identified that cause variation among different populations and even within individuals of a similar descent. This leads to interindividual variations in the optimal dose of the drug that is required to sustain the treatment efficiency. In this study, 56 single nucleotide polymorphisms (SNPs) within several pharmacogenes were analyzed in 128 unrelated subjects from a genetically isolated group of Circassian people living in Jordan. We also compared these variant distributions to other ethnic groups that are available at two databases (Genome 1000 and eXAC). Our results revealed that the distribution of allele frequencies within genes among Circassians in Jordan showed similarities and disparities when compared to other populations. This study provides a powerful base for clinically relevant SNPs to enhance medical research and future pharmacogenomic studies. Rare variants detected in isolated populations can significantly guide to novel loci involved in the development of clinically relevant traits.

PMID: 31935801 [PubMed]

High Loading of Hydrophobic and Hydrophilic Agents via Small Immunostimulatory Carrier for Enhanced Tumor Penetration and Combinational Therapy.

Theranostics. 2020;10(3):1136-1150

Authors: Sun J, Chen Y, Xu J, Song X, Wan Z, Du Y, Ma W, Li X, Zhang L, Li S

Abstract
Development of small-sized nanoformulations for effective tumor penetration, particularly for those tumors with dense stroma is a major challenge in cancer nanomedicine. It is even more challenging to achieve effective co-loading of both hydrophobic and hydrophilic anticancer agents through a small-sized nanocarrier. In this work, we designed a novel redox-responsive gemcitabine (GEM)-conjugated polymer POEG-co-PVDGEM (PGEM) as a small-sized nanocarrier to co-deliver hydrophilic GEM and hydrophobic paclitaxel (PTX). Methods: The in vitro physicochemical and biological properties of PTX/PGEM NPs were characterized. The efficiency of the PGEM carrier in selective codelivery of GEM and PTX in two murine tumor models as well as a patient derived xenograft model (PDX) was also evaluated. In addition, we investigated the changes in tumor immune microenvironment after treatment with PTX/PGEM nanoparticles. Results: We discovered that GEM conjugation could significantly decrease the nanoparticle size from 160 nm to 13 nm. Moreover, different from most reported GEM-conjugated polymers, PGEM polymer could serve as a prodrug carrier to load a wide variety of hydrophobic agents with high drug loading capacity and excellent stability. More importantly, our strategy could be extended to various nucleotides-based drugs such as azacytidine, decitabine and cytarabine, suggesting a new platform for co-delivery of various first line hydrophilic and hydrophobic anticancer agents. Imaging showed that our small-sized carrier was much more effective in tumor accumulation and penetration compared to the relatively large-sized drug carrier. The PGEM prodrug-based carrier not only well retained the pharmacological activity of GEM, but also boosted T-cell immune response. Furthermore, delivery of PTX via PGEM led to significantly improved antitumor activity in several murine cancer models and a PDX model of colon cancer. Conclusion: This work not only provided a small-sized carrier platform that was able to load multiple hydrophilic and hydrophobic drugs with high loading capacity, but also provided an effective regimen for enhanced tumor penetration and improved anti-tumor immunity.

PMID: 31938056 [PubMed - in process]

Current state assessment survey of challenges of pharmacogenomics within oncology pharmacy practice.

J Oncol Pharm Pract. 2020 Jan 14;:1078155219896395

Authors: Przybylski DJ, Dow-Hillgartner EN, Reed MP, Fallon MJ

PMID: 31937189 [PubMed - as supplied by publisher]

Macrophage Phosphoproteome Analysis Reveals MINCLE-dependent and -independent Mycobacterial Cord Factor Signaling.

Mol Cell Proteomics. 2019 04;18(4):669-685

Authors: Hansen M, Peltier J, Killy B, Amin B, Bodendorfer B, Härtlova A, Uebel S, Bosmann M, Hofmann J, Büttner C, Ekici AB, Kuttke M, Franzyk H, Foged C, Beer-Hammer S, Schabbauer G, Trost M, Lang R

Abstract
Immune sensing of Mycobacterium tuberculosis relies on recognition by macrophages. Mycobacterial cord factor, trehalose-6,6'-dimycolate (TDM), is the most abundant cell wall glycolipid and binds to the C-type lectin receptor (CLR) MINCLE. To explore the kinase signaling linking the TDM-MINCLE interaction to gene expression, we employed quantitative phosphoproteome analysis. TDM caused upregulation of 6.7% and suppressed 3.8% of the 14,000 phospho-sites identified on 3727 proteins. MINCLE-dependent phosphorylation was observed for canonical players of CLR signaling (e.g. PLCγ, PKCδ), and was enriched for PKCδ and GSK3 kinase motifs. MINCLE-dependent activation of the PI3K-AKT-GSK3 pathway contributed to inflammatory gene expression and required the PI3K regulatory subunit p85α. Unexpectedly, a substantial fraction of TDM-induced phosphorylation was MINCLE-independent, a finding paralleled by transcriptome data. Bioinformatics analysis of both data sets concurred in the requirement for MINCLE for innate immune response pathways and processes. In contrast, MINCLE-independent phosphorylation and transcriptome responses were linked to cell cycle regulation. Collectively, our global analyses show substantial reprogramming of macrophages by TDM and reveal a dichotomy of MINCLE-dependent and -independent signaling linked to distinct biological responses.

PMID: 30635358 [PubMed - indexed for MEDLINE]

Effect of Environmental Exposure and Pharmacogenomics on Drug Metabolism.

Curr Drug Metab. 2020 Jan 10;:

Authors: Banerjee BD, Kumar R, Thamineni KL, Shah H, Thakur GK, Sharma T

Abstract
BACKGROUND: Pesticides are major xenobiotic compounds and environmental pollutants, which are able to alter drug-metabolizing enzyme as well as pharmacokinetics of drugs. Subsequent to the release of the human genome project, genetic variations (polymorphism) became an integral part of drug development due to its influence on disease susceptibility/ progression of the disease and their impact on drug absorption, distribution, metabolism of active metabolites and finally excretion of the drug. Genetic polymorphisms crucially regulate pharmacokinetics and pharmacodynamics of drugs under the influence of physiological condition, lifestyle, as well as pathological conditions collectively.
OBJECTIVE: To review all the evidences concerning the effect of environmental exposure on drug metabolism with reference to pharmacogenomics.
METHOD: Scientific data search and review of basic, epidemiological, pharmacogenomics and pharmacokinetics studies evaluating the influence of environmental contaminant on drug metabolism.
RESULT: Various environmental contaminants like pesticides effectively alter drug metabolism at various levels under the influence of pharmacogenomics which interferes pharmacokinetics of the drug metabolism. Genetic polymorphism of phase I and phase II xenobiotic-metabolizing enzymes remarkably alter disease susceptibility as well as the progression of disease under the influence of various environmental contaminants at various levels.
CONCLUSION: Individual specific drug response may be attributed to a large variety of factors alone or in combination ranging from genetic variations (SNP, insertion, deletion, duplication etc.) to physiological setting (gender, age, body size, and ethnicity), environmental or lifestyle factors (radiation exposure, smoking, alcohol, nutrition, exposure to toxins, etc.); and pathological conditions (obesity, diabetes, liver and renal function).

PMID: 31933442 [PubMed - as supplied by publisher]

Causative drugs for drug-induced cutaneous reactions in central China: a 608-case analysis.

An Bras Dermatol. 2019 Nov - Dec;94(6):664-670

Authors: Zhao J, Hu L, Zhang L, Zhou M, Gao L, Cheng L

Abstract
BACKGROUND: Reports regarding the causative drugs of drug-induced cutaneous adverse reactions in China are indistinct, such that different regions have reported the spectrum of drugs differs substantially in different clinical conditions.
OBJECTIVE: To explore the causative drugs that led to cutaneous reactions.
METHODS: Adverse drug reaction reports from central China were collected and divided into cutaneous adverse reactions and severe cutaneous adverse reactions groups. Cases were reviewed retrospectively for causative drugs.
RESULTS: The male:female ratio was equal in both cutaneous adverse reactions and severe cutaneous adverse reactions. In cutaneous adverse reactions (n=482), the highest incidence happened between 51 and 60 years of age and the top three causative drugs were antibiotics (48%), Chinese medicine (16%), and allopurinol (9%). In severe cutaneous adverse reactions (n=126), the highest incidence happened between 41 and 50 years of age and the top three causative drugs were sedative-hypnotics and antiepileptics (39%), antibiotics (22%), and allopurinol (15%). Carbamazepine was the most frequently used single-drug (16/18) in sedative-hypnotics and antiepileptics. β-lactams were the most frequently used antibiotics that induced both cutaneous adverse reactions and severe cutaneous adverse reactions.
STUDY LIMITATIONS: The small sample size, retrospective design, collection of cutaneous adverse reactions and severe cutaneous adverse reactions at different time frames and locations, and exclusion of patients taking more than five medications are limitations of the study.
CONCLUSIONS: Gender does not affect cutaneous adverse reactions and severe cutaneous adverse reactions. The top three drugs to induce cutaneous adverse reactions are antibiotics, Chinese medicine, and allopurinol, while those that triggered severe cutaneous adverse reactions are sedative-hypnotics and antiepileptics, antibiotics, and allopurinol. Carbamazepine is the most frequent single drug that induces severe cutaneous adverse reactions. β-lactams are the most frequently used antibiotics that induce both cutaneous adverse reactions and severe cutaneous adverse reactions.

PMID: 31789251 [PubMed - indexed for MEDLINE]

Computational analyses prioritize and reveal the deleterious nsSNPs in human angiotensinogen gene.

Comput Biol Chem. 2020 Jan 07;84:107199

Authors: Goswami AM

Abstract
Angiotensinogen (AGT) is a key component of renin-angiotensin-aldosterone system (RAAS), which plays central role in blood pressure homeostasis. Association of AGT polymorphisms have been investigated in different ethnic populations in variety of cardiovascular and non-cardiovascular conditions. In this study, 354 non-synonymous SNPs (nsSNPs) of AGT were evaluated to predict damaging and structurally important variants. Majority of the deleterious nsSNPs occurred in the evolutionary conserved regions. Several of these nsSNPs were found to affect post-translational modifications like methylation, glycosylation, phosphorylation, ubiquitination etc. Structural evaluations predicted 19 variants as destabilizing and some of them were also predicted to destabilize the renin-AGT interaction. Therefore, the present computational investigation predicted pathogenic and functionally important variants of human AGT gene. The study has also shown that AGT deregulation is associated with survival outcome in patients with gastric and breast cancer, using microarray gene expression profile. Furthermore, the computationally screened nsSNPs can be analyzed in population based genotyping studies and may help futuristic drug development in the area of AGT pharmacogenomics.

PMID: 31931433 [PubMed - as supplied by publisher]

Inflammation factors and element supplementation in cancer.

J Trace Elem Med Biol. 2020 Jan 08;59:126450

Authors: Jelińska M, Skrajnowska D, Wrzosek M, Domanska K, Bielecki W, Zawistowska M, Bobrowska Korczak B

Abstract
The aim of the study was to evaluate the effect of dietary supplementation with chosen minerals (Zn, Se, Fe) on expression of selected cytokines (IL-1, IL-6, TNFα) in spleen of rats and on their concentrations in rat serum under inflammatory and pathological conditions obtained by implantation of prostate cancer cells (LnCaP). Serum levels of metabolites of arachidonic, eicosapentaenoic and linoleic acids (hydroxyeicosatetraenoic, hydroxyeicosapentaenoic and hydroxyoctadecadienoic acids, respectively), as compounds involved in inflammation and cancer development, were also investigated. Male rats were randomised into dietary groups supplemented with Zn, Se or Fe. Prostate cancer cells were implanted to some rats in each group. The study demonstrated that minerals supplemented with the diet may exert various effects on an organism. Selenium, zinc and iron influence pro-inflammatory cytokine expression, what leads to stimulation of inflammation. They also affect synthesis of arachidonic and linoleic acid metabolites that exert pro-inflammatory action and enable cancer development and metastasis.

PMID: 31931255 [PubMed - as supplied by publisher]

Negligible-Cost and Weekend-Free Chemically Defined Human iPSC Culture.

Stem Cell Reports. 2020 Jan 09;:

Authors: Kuo HH, Gao X, DeKeyser JM, Fetterman KA, Pinheiro EA, Weddle CJ, Fonoudi H, Orman MV, Romero-Tejeda M, Jouni M, Blancard M, Magdy T, Epting CL, George AL, Burridge PW

Abstract
Human induced pluripotent stem cell (hiPSC) culture has become routine, yet the cost of pluripotent cell media, frequent medium changes, and the reproducibility of differentiation have remained restrictive. Here, we describe the formulation of a hiPSC culture medium (B8) as a result of the exhaustive optimization of medium constituents and concentrations, establishing the necessity and relative contributions of each component to the pluripotent state and cell proliferation. The reagents in B8 represent only 3% of the costs of commercial media, made possible primarily by the in-lab generation of three E. coli-expressed, codon-optimized recombinant proteins: fibroblast growth factor 2, transforming growth factor β3, and neuregulin 1. We demonstrate the derivation and culture of 34 hiPSC lines in B8 as well as the maintenance of pluripotency long term (over 100 passages). This formula also allows a weekend-free feeding schedule without sacrificing capacity for differentiation.

PMID: 31928950 [PubMed - as supplied by publisher]

A review of the pharmacology and toxicology of aucubin.

Fitoterapia. 2020 Jan;140:104443

Authors: Zeng X, Guo F, Ouyang D

Abstract
Aucubin is an iridoid glycoside that is widely prevalent in traditional medicinal herbs, such as Eucommia ulmoides Oliv., Aucuba japonica Thunb. and Plantago asiatica L. This review aims to provide a comprehensive summary of the source, biological activity, pharmacokinetics and toxicology of aucubin with the ultimate objective of providing a guide for future drug development and potential clinical applications of aucubin. Aucubin is a highly active compound possessing extensive biological effects including antioxidant, anti-aging, anti-inflammatory, anti-fibrotic, anti-cancer, hepatoprotective, neuroprotective and osteoprotective properties. Although aucubin has been shown to have poor oral bioavailability in rats, aucubin is widely distributed in multiple organs including kidney, liver, heart, spleen and lung, and there is a sex difference in the absorption of aucubin. Tolerance of aucubin is good and no serious adverse reactions have been observed to date. In short, aucubin is a compound with abundant potential sources, good safety and numerous beneficial biological activities, which exhibits high potential value for use in health care products and pharmaceuticals. In order to accelerate the development and utilization of aucubin-related products, in-depth studies should be focused on the following questions of interest. First, it is necessary to introduce advanced separation and formulation technologies to improve the yield and stability of aucubin products. Second, studies should focus on the specific pharmacological activities of aucubin to determine the structure-activity relationship so as to improve the efficacy and reduce side effects. Finally, clinical studies are needed to confirm the efficacy of aucubin in specific diseases.

PMID: 31790767 [PubMed - indexed for MEDLINE]

Coupling the near-infrared fluorescent dye IR-780 with cabazitaxel makes renal cell carcinoma chemotherapy possible.

Biomed Pharmacother. 2019 Aug;116:109001

Authors: Zheng Y, Lan T, Wei D, Zhang G, Hou G, Yuan J, Yan F, Wang F, Meng P, Yang X, Chen G, Zhu Z, Lu Z, He W, Yuan J

Abstract
Renal cell carcinoma (RCC) has always been considered resistant to chemotherapy. IR-780 is a near-infrared fluorescent (NIRF) dye that can be efficiently taken up by RCC cells. Cabazitaxel is a cytotoxic drug that interferes with mitosis by acting on tubulin. We chemically fused IR-780 and cabazitaxel into a new drug, Caba-780, which is expected to increase the sensitivity of RCC to chemotherapy. Infrared spectrum, nuclear magnetic resonance spectra, high-resolution mass spectra, and IR spectra were used for detecting structural characterization of the new synthetic drug Caba-780. The RCC cells lines ACHN and 786-O, as well as the non-cancerous human embryonic kidney cell line HEK293, were used to assess the cytotoxicity and tumor-efficient uptake of Caba-780 in vitro. The xenograft tumor-bearing mice and C57 mice were used to estimate the tumor-efficient imaging of Caba-780 as well as the safety and efficacy of its anti-tumor effects in vivo. The new synthetic drug Caba-780 retains the NIRF properties of IR-780. In vitro, Caba-780 was efficiently absorbed by the RCC cell lines ACHN and 786-O, and had an inhibitory effect on their growth, clonogenicity migration, and invasion. At the same time, Caba-780 retained the anti-tumor effect of cabazitaxel, which can inhibit the growth of tumor cells and promote apoptosis by inhibiting mitosis. In vivo experiments showed that Caba-780 can be taken up and imaged in tumor tissue, whereby it inhibits tumor growth. The novel fused molecule Caba-780 has application prospects in the diagnosis and treatment of RCC and makes RCC chemotherapy possible.

PMID: 31146114 [PubMed - indexed for MEDLINE]

Inhibition of mTORC1/P70S6K pathway by Metformin synergistically sensitizes Acute Myeloid Leukemia to Ara-C.

Life Sci. 2020 Jan 08;:117276

Authors: Yuan F, Cheng C, Xiao F, Liu H, Cao S, Zhou G

Abstract
AIMS: Chemo-resistance still was the main obstacle for AML patients, more effective and less toxic forms of therapies were desperately needed. Metformin, a classic hypoglycemic drug for diabetes recently delivered us a new identity that it exerted anti-tumor activity through suppressing mTOR in various tumors. But the anti-tumor effect of metformin in AML was not clear.
METHODS: In this study, we used CCK8 assay and apoptosis assay to determine the anti-leukemia activity of metformin combined with AraC, and explore the mechanism of the joint role of Ara-C/metformin in AML. We finally used xenograft experiment in mice to determine the anti-leukemia effect of Ara-C/metformin in vivo.
KEY FINDINGS: We found that metformin could synergistically sensitize AML cells to Ara-C via inhibiting mTORC1/P70S6K pathway. In vivo experiment also verified metformin in aid of Ara-C caused an obviously synergistic anti-tumor effect.
SIGNIFICANCE: We firstly found the synergistic anti-tumor effect of Ara-C/metformin in AML through inhibiting mTORC1/P70S6K pathway.

PMID: 31926250 [PubMed - as supplied by publisher]

Anxiety Symptoms Questionnaire (ASQ): development and validation.

Gen Psychiatr. 2019;32(6):e100144

Authors: Baker A, Simon N, Keshaviah A, Farabaugh A, Deckersbach T, Worthington JJ, Hoge E, Fava M, Pollack MP

Abstract
Background: The Anxiety Symptoms Questionnaire (ASQ) is a brief self-report questionnaire which measures frequency and intensity of symptoms and was developed to improve assessment of anxiety symptoms in a clinical setting. We examined the reliability and validity of the ASQ in patients with anxiety disorders and/or depression, non-clinical control subjects and college students.
Methods: 240 outpatients with generalised anxiety disorder, social anxiety disorder, panic disorder or major depressive disorder were administered the ASQ and additional questionnaires measuring depression and anxiety, as were 111 non-clinical control subjects and 487 college students. Factor analysis, Pearson's correlation coefficients and logistic regression were used to assess reliability and validity. Test-retest reliability of the ASQ was measured using a subset who were re-administered the ASQ after 4 weeks.
Results: Factor analysis revealed measurement of a single dimension by the ASQ. Internal consistency and test-retest reliability were strong. The ASQ total score also significantly distinguished patients with an anxiety disorder from the clinical controls above and beyond the clinician-rated Hamilton Anxiety Scale.
Conclusions: The ASQ is a valid, reliable and effective self-rated measure of anxiety and may be a useful tool for screening and assessing anxiety symptoms in psychiatric as well as college settings.

PMID: 31922090 [PubMed]

Precision Medicine in Lymphoma by Innovative Instrumental Platforms.

Front Oncol. 2019;9:1417

Authors: Di Paolo A, Arrigoni E, Luci G, Cucchiara F, Danesi R, Galimberti S

Abstract
In recent years, many efforts have been addressed to the growing field of precision medicine in order to offer individual treatments to every patient on the basis of his/her genetic background. Formerly adopted to achieve new disease classifications as it is still done, innovative platforms, such as microarrays, genome-wide association studies (GWAS), and next generation sequencing (NGS), have made the progress in pharmacogenetics faster and cheaper than previously expected. Several studies in lymphoma patients have demonstrated that these platforms can be used to identify biomarkers predictive of drug efficacy and tolerability, discovering new possible druggable proteins. Indeed, GWAS and NGS allow the investigation of the human genome, finding interesting associations with putative or unexpected targets, which in turns may represent new therapeutic possibilities. Importantly, some objective difficulties have initially hampered the translation of findings in clinical routines, such as the poor quantity/quality of genetic material or the paucity of targets that could be investigated at the same time. At present, some of these technical issues have been partially solved. Furthermore, these analyses are growing in parallel with the development of bioinformatics and its capabilities to manage and analyze big data. Because of pharmacogenetic markers may become important during drug development, regulatory authorities (i.e., EMA, FDA) are preparing ad hoc guidelines and recommendations to include the evaluation of genetic markers in clinical trials. Concerns and difficulties for the adoption of genetic testing in routine are still present, as well as affordability, reliability and the poor confidence of some patients for these tests. However, genetic testing based on predictive markers may offers many advantages to caregivers and patients and their introduction in clinical routine is justified.

PMID: 31921674 [PubMed]

Developmental Pharmacogenetics of SLCO2B1 on Montelukast Pharmacokinetics in Chinese Children.

Drug Des Devel Ther. 2019;13:4405-4411

Authors: Li Q, Wang K, Shi HY, Wu YE, Zhou Y, Kan M, Zheng Y, Hao GX, Yang XM, Yang YL, Su LQ, Wang XL, Jacqz-Aigrain E, Zhou J, Zhao W

Abstract
Background: Montelukast, a potent oral selective leukotriene-receptor antagonist, inhibits the action of cysteinyl-leukotriene in patients with asthma. Although pharmacokinetic studies of montelukast have been reported in Caucasian adults and children, and showed large inter-individual variability on pharmacokinetics, none of these studies has been explored in Chinese children. Given the potential inter-ethnic difference, the purpose of the present study was to evaluate the effects of developmental factors and pharmacogenetics of CYP2C8 and SLCO2B1 on montelukast clearance in Chinese pediatric patients.
Methods: After the administration of montelukast, blood samples were collected from children and plasma concentrations were determined using an adapted micro high-performance liquid chromatography coupled with the fluorescence detection (HPLC-FLD) method. A previously published pharmacokinetic model was validated using the opportunistic pharmacokinetic samples, and individual patient's clearance was calculated using the validated model. Population pharmacokinetic analysis was performed using a nonlinear mixed-effects model approach (NONMEM V 7.2.0) and variants of CYP2C8 and SLCO2B1 were genotyped.
Results: Fifty patients (age range: 0.7-10.0 years) with asthma were enrolled in this study. The clearance of montelukast was significantly higher in children with the SLCO2B1 c.935GA and c.935AA genotypes compared with that of children with the SLCO2B1 c.935GG genotype (0.94 ± 0.26 versus 0.77 ± 0.21, p = 0.020). The patient's weight was also found to be significantly corrected with montelukast clearance (p <0.0001).
Conclusion: The developmental pharmacology of montelukast in Chinese children was evaluated. Weight and SLCO2B1 genotype were found to have independent significant impacts on the clearance of montelukast.

PMID: 31920289 [PubMed - in process]

Pharmacogenomics of poor drug metabolism in Greyhounds: Cytochrome P450 (CYP) 2B11 genetic variation, breed distribution, and functional characterization.

Sci Rep. 2020 Jan 09;10(1):69

Authors: Martinez SE, Andresen MC, Zhu Z, Papageorgiou I, Court MH

Abstract
Greyhounds recover more slowly from certain injectable anesthetics than other dog breeds. Previous studies implicate cytochrome P450 (CYP) 2B11 as an important clearance mechanism for these drugs and suggest Greyhounds are deficient in CYP2B11. However, no CYP2B11 gene mutations have been identified that explain this deficiency in Greyhounds. The objectives of this study were to provide additional evidence for CYP2B11 deficiency in Greyhounds, determine the mechanisms underlying this deficiency, and identify CYP2B11 mutations that contribute to this phenotype in Greyhounds. Greyhound livers metabolized CYP2B11 substrates slower, possessed lower CYP2B11 protein abundance, but had similar or higher mRNA expression than other breeds. Gene resequencing identified three CYP2B11 haplotypes, H1 (reference), H2, and H3 that were differentiated by mutations in the gene 3'-untranslated region (3'-UTR). Compared with 63 other dog breeds, Greyhounds had the highest CYP2B11-H3 allele frequency, while CYP2B11-H2 was widely distributed across most breeds. Using 3'-UTR luciferase reporter constructs, CYP2B11-H3 showed markedly lower gene expression (over 70%) compared to CYP2B11-H1 while CYP2B11-H2 expression was intermediate. Truncated mRNA transcripts were observed in CYP2B11-H2 and CYP2B11-H3 but not CYP2B11-H1 transfected cells. Our results implicate CYP2B11 3'-UTR mutations as a cause of decreased CYP2B11 enzyme expression in Greyhounds through reduced translational efficiency.

PMID: 31919457 [PubMed - in process]

Discussion.

Surgery. 2019 10;166(4):481-482

Authors:

PMID: 31320225 [PubMed - indexed for MEDLINE]