Pharmacokinetics of fixed-dose combination of atorvastatin and metformin compared with individual tablets.

Drug Des Devel Ther. 2019;13:1623-1632

Authors: Ghim JL, Phuong NTT, Kim MJ, Kim EJ, Song GS, Ahn S, Shin JG, Kim EY

Abstract
Purpose: The aims of this study was to investigate the mutual pharmacokinetic interactions between steady-state atorvastatin and metformin and the effect of food on the fixed-dose combined (FDC) tablet of atorvastatin and metformin extended release (XR). Subjects and methods: Study 1, an open-labeled, fixed sequence, multiple-dose pharmacokinetic drug-drug interaction study, was divided into 2 parts. Atorvastatin (40 mg) or metformin (1,000 mg) XR tablets were administered once daily via mono- or co-therapy for 7 days. Plasma levels of atorvastatin and 2-OH-atorvastatin, were quantitatively determined for 36 h in part A (n=50) while metformin plasma concentration was measured up to 24 h in part B (n=16) after the last dosing. Study 2, a randomized, open-labeled, single-dose, two-treatment, two-period, two-sequence crossover study, involved 27 healthy subjects to investigate the impact of food intake on the pharmacokinetics of a combined atorvastatin/metformin XR 20/500 mg (CJ-30056 20/500 mg) tablet. Results: After multiple doses of mono- or co-therapy of atorvastatin (40 mg) and metformin (1,000 mg) XR, the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) for the peak plasma concentration at steady state (Cmax,ss) and area under the plasma concentration-time curve during the dosing interval at steady state (AUCτ,ss) were 1.07 (0.94-1.22) and 1.05 (0.99-1.10) for atorvastatin, 1.06 (0.96-1.16) and 1.16 (1.10-1.21) for 2-OH-atorvastatin, and 1.00 (0.86-1.18) and 0.99 (0.87-1.13) for metformin, respectively. Food delayed time to reach maximum concentration (tmax), decreased atorvastatin Cmax by 32% with a GMR (90% CI) of 0.68 (0.59-0.78), and increased metformin AUCt by 56% with a GMR (90% CI) of 1.56 (1.43-1.69). Conclusion: No clinically relevant pharmacokinetic interaction was seen when atorvastatin was co-administered with metformin. Food appeared to change the absorption of atorvastatin and metformin from an FDC formulation. These alterations were in accordance with those described with the single reference drugs when ingested with food.

PMID: 31190741 [PubMed - indexed for MEDLINE]

Constitutive Activation of the Human Aryl Hydrocarbon Receptor in Mice Promotes Hepatocarcinogenesis Independent of Its Coactivator Gadd45b.

Toxicol Sci. 2019 02 01;167(2):581-592

Authors: Lu P, Cai X, Guo Y, Xu M, Tian J, Locker J, Xie W

Abstract
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), or dioxin, is a potent liver cancer promoter through its sustained activation of the aryl hydrocarbon receptor (Ahr) in rodents. However, the carcinogenic effect of TCDD and AHR in humans has been controversial. It has been suggested that the inter-species difference in the carcinogenic activity of AhR is largely due to different ligand affinity in that TCDD has a 10-fold lower affinity for the human AHR compared with the mouse Ahr. It remains unclear whether the activation of human AHR is sufficient to promote hepatocellular carcinogenesis. The goal of this study is to clarify whether activation of human AHR can promote hepatocarcinogenesis. Here we reported the oncogenic activity of human AHR in promoting hepatocellular carcinogenesis. Constitutive activation of the human AHR in transgenic mice was as efficient as its mouse counterpart in promoting diethylnitrosamine (DEN)-initiated hepatocellular carcinogenesis. The growth arrest and DNA damage-inducible gene 45 β (Gadd45b), a signaling molecule inducible by external stress and UV irradiation, is highly induced upon AHR activation. Further analysis revealed that Gadd45b is a novel AHR target gene and a transcriptional coactivator of AHR. Interestingly, ablation of Gadd45b in mice did not abolish the tumor promoting effects of the human AHR. Collectively, our findings suggested that constitutive activation of human AHR was sufficient to promote hepatocarcinogenesis.

PMID: 30346592 [PubMed - indexed for MEDLINE]

Multiple genetic factors affecting the pharmacokinetic and pharmacodynamic processes of tacrolimus in Chinese myasthenia gravis patients.

Eur J Clin Pharmacol. 2020 Jan 18;:

Authors: Meng HY, Li X, Jin WL, Yan CK, Dong XH, Xu Q, Peng YY, Li ZB, Li Y, Luo ZH, Xu LQ, Yang H

Abstract
PURPOSE: Tacrolimus is a novel effective immunosuppressant for myasthenia gravis (MG) patients. However, the narrow therapeutic window, and high inter- and intrapatient variation in bioavailability largely limited its clinical application. This article intended to find the SNPs influencing clinical outcome and discover the possible mechanisms.
METHODS: Based on the tagSNPs genotyped by Improved Multiple Ligase Detection Reaction, Plink 1.07 was used to find the SNPs having close interaction to tacrolimus serum concentration, QMG score changes or even reasonable drug dose. Then we searched several databases to predict the possible miRNA binding rs15524 sequence. Based on the prediction, dual-luciferase reporter assay and miRNA transfection were used to discover the mechanism of how SNP rs15524 controls tacrolimus serum concentration through influencing CYP3A5 expression.
RESULTS: In this article, we found multiple SNPs on CYP3A4, CYP3A5, FKBP1A, NFATC2 genes were predicted closely related to tacrolimus serum concentration, therapeutic effect which reflected by QMG score changes or even reasonable drug dose. After in silico miRNA selection, possible relationship between hsa-miR-500a and rs15524 was found. With the help of dual-luciferase reporter assay, wild-type rs15524 (T allele) was found having a stronger binding affinity for hsa-miR-500a. Higher expression of CYP3A5 may also led by lower hsa-miR-500a level.
CONCLUSIONS: SNP rs15524 may control CYP3A5 expression by affecting the binding affinity between CYP3A5 3'UTR and hsa-miR-500a. Wild type (T allele) 3'UTR of CYP3A5 has stronger binding affinity to hsa-miR-500a and cause lower CYP3A5 expression and higher tacrolimus serum concentration.

PMID: 31955224 [PubMed - as supplied by publisher]

Validation study of microRNAs previously associated with antidepressant response in older adults treated for late-life depression with venlafaxine.

Prog Neuropsychopharmacol Biol Psychiatry. 2020 Jan 16;:109867

Authors: Marshe VS, Islam F, Maciukiewicz M, Fiori LM, Yerko V, Yang J, Turecki G, Foster JA, Kennedy SH, Blumberger DM, Karp JF, Kennedy JL, Mulsant BH, Reynolds CF, Lenze EJ, Müller DJ

Abstract
BACKGROUND: MicroRNAs (miRNAs) are small 22 nucleotides long, non-coding RNAs that are potential biomarkers for antidepressant treatment response. We aimed to replicate previous associations of miRNAs with antidepressant treatment response in a sample of older adults diagnosed with late-life depression.
METHODS: Our sample included 184 older adults diagnosed with moderately severe depression that received open-label venlafaxine (up to 300 mg/day) for approximately 12 weeks. We quantified miRNA expression levels at baseline and week 12 for miRNAs miR-1202, miR-135a-5p, miR-16-5p, miR-146a-5p, miR-146b-5p, miR-425-3p, and miR-24-3p to explore their association with remission status, response trajectories, and time-to-remission.
RESULTS: At T0 and T12, there were no differences in miRNA expression levels between remitters and non-remitters. However, remitters showed a trend toward higher baseline miR-135a-5p (Median = 11.3 [9.9, 15.7], p = .083). Prior to correction, baseline miR-135a-5p expression levels showed an association with remission status (OR = 1.8 [1.0, 3.3], p = .037). Individuals with higher baseline miR-135a-5p showed better response trajectories (F = 4.5, FDR-corrected p = 4.4 × 10-4), particularly at weeks 10 and 12 (p < .05). In addition, individuals with higher miR-135a-5p expression reached remission faster than those with lower expression (HR = 0.6 [0.4, 0.9], FDR-corrected p = .055).
LIMITATIONS: Although the sample size was relatively modest, our findings are consistent with the literature suggesting that higher miR-135a-5p levels may be associated with better antidepressant treatment response.
CONCLUSIONS: However, the miRNA signature of antidepressant response in older adults may be different as compared to younger adults.

PMID: 31954757 [PubMed - as supplied by publisher]

Dopamine-Evoked Synaptic Regulation in the Nucleus Accumbens Requires Astrocyte Activity.

Neuron. 2020 Jan 07;:

Authors: Corkrum M, Covelo A, Lines J, Bellocchio L, Pisansky M, Loke K, Quintana R, Rothwell PE, Lujan R, Marsicano G, Martin ED, Thomas MJ, Kofuji P, Araque A

Abstract
Dopamine is involved in physiological processes like learning and memory, motor control and reward, and pathological conditions such as Parkinson's disease and addiction. In contrast to the extensive studies on neurons, astrocyte involvement in dopaminergic signaling remains largely unknown. Using transgenic mice, optogenetics, and pharmacogenetics, we studied the role of astrocytes on the dopaminergic system. We show that in freely behaving mice, astrocytes in the nucleus accumbens (NAc), a key reward center in the brain, respond with Ca2+ elevations to synaptically released dopamine, a phenomenon enhanced by amphetamine. In brain slices, synaptically released dopamine increases astrocyte Ca2+, stimulates ATP/adenosine release, and depresses excitatory synaptic transmission through activation of presynaptic A1 receptors. Amphetamine depresses neurotransmission through stimulation of astrocytes and the consequent A1 receptor activation. Furthermore, astrocytes modulate the acute behavioral psychomotor effects of amphetamine. Therefore, astrocytes mediate the dopamine- and amphetamine-induced synaptic regulation, revealing a novel cellular pathway in the brain reward system.

PMID: 31954621 [PubMed - as supplied by publisher]

Cost-Effectiveness of Multigene Pharmacogenetic Testing in Patients With Acute Coronary Syndrome After Percutaneous Coronary Intervention.

Value Health. 2020 Jan;23(1):61-73

Authors: Dong OM, Wheeler SB, Cruden G, Lee CR, Voora D, Dusetzina SB, Wiltshire T

Abstract
OBJECTIVE: To evaluate the cost-effectiveness of multigene testing (CYP2C19, SLCO1B1, CYP2C9, VKORC1) compared with single-gene testing (CYP2C19) and standard of care (no genotyping) in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) from Medicare's perspective.
METHODS: A hybrid decision tree/Markov model was developed to simulate patients post-PCI for ACS requiring antiplatelet therapy (CYP2C19 to guide antiplatelet selection), statin therapy (SLCO1B1 to guide statin selection), and anticoagulant therapy in those that develop atrial fibrillation (CYP2C9/VKORC1 to guide warfarin dose) over 12 months, 24 months, and lifetime. The primary outcome was cost (2016 US dollar) per quality-adjusted life years (QALYs) gained. Costs and QALYs were discounted at 3% per year. Probabilistic sensitivity analysis (PSA) varied input parameters (event probabilities, prescription costs, event costs, health-state utilities) to estimate changes in the cost per QALY gained.
RESULTS: Base-case-discounted results indicated that the cost per QALY gained was $59 876, $33 512, and $3780 at 12 months, 24 months, and lifetime, respectively, for multigene testing compared with standard of care. Single-gene testing was dominated by multigene testing at all time horizons. PSA-discounted results indicated that, at the $50 000/QALY gained willingness-to-pay threshold, multigene testing had the highest probability of cost-effectiveness in the majority of simulations at 24 months (61%) and over the lifetime (81%).
CONCLUSIONS: On the basis of projected simulations, multigene testing for Medicare patients post-PCI for ACS has a higher probability of being cost-effective over 24 months and the lifetime compared with single-gene testing and standard of care and could help optimize medication prescribing to improve patient outcomes.

PMID: 31952675 [PubMed - in process]

Pharmacogenomics at the center of precision medicine: challenges and perspective in an era of Big Data.

Pharmacogenomics. 2020 Jan 17;:

Authors: Primorac D, Bach-Rojecky L, Vađunec D, Juginović A, Žunić K, Matišić V, Skelin A, Arsov B, Boban L, Erceg D, Ivkošić IE, Molnar V, Ćatić J, Mikula I, Boban L, Primorac L, Esquivel B, Donaldson M

Abstract
Pharmacogenomics (PGx) is one of the core elements of personalized medicine. PGx information reduces the likelihood of adverse drug reactions and optimizes therapeutic efficacy. St Catherine Specialty Hospital in Zagreb/Zabok, Croatia has implemented a personalized patient approach using the RightMed® Comprehensive PGx panel of 25 pharmacogenes plus Facor V Leiden, Factor II and MTHFR genes, which is interpreted by a special counseling team to offer the best quality of care. With the advent of significant technological advances comes another challenge: how can we harness the data to inform clinically actionable measures and how can we use it to develop better predictive risk models? We propose to apply the principles artificial intelligence to develop a medication optimization platform to prevent, manage and treat different diseases.

PMID: 31950879 [PubMed - as supplied by publisher]

Pharmacogenomic associations of adverse drug reactions in asthma: systematic review and research prioritisation.

Pharmacogenomics J. 2020 Jan 17;:

Authors: King C, McKenna A, Farzan N, Vijverberg SJ, van der Schee MP, Maitland-van der Zee AH, Arianto L, Bisgaard H, BØnnelykke K, Berce V, Potočnik U, Repnik K, Carleton B, Daley D, Chew FT, Chiang WC, Sio YY, Cloutier MM, Den Dekker HT, Duijts L, de Jongste JC, Dijk FN, Koppelman GH, Flores C, Hernandez-Pacheco N, Pino-Yanes M, Mukhopadhyay S, Basu K, Bignell L, Tantisira KG, Turner S, Verhamme KM, Francis B, Pirmohamed M, Sinha I, Hawcutt DB

Abstract
A systematic review of pharmacogenomic studies capturing adverse drug reactions (ADRs) related to asthma medications was undertaken, and a survey of Pharmacogenomics in Childhood Asthma (PiCA) consortia members was conducted. Studies were eligible if genetic polymorphisms were compared with suspected ADR(s) in a patient with asthma, as either a primary or secondary outcome. Five studies met the inclusion criteria. The ADRs and polymorphisms identified were change in lung function tests (rs1042713), adrenal suppression (rs591118), and decreased bone mineral density (rs6461639) and accretion (rs9896933, rs2074439). Two of these polymorphisms were replicated within the paper, but none had external replication. Priorities from PiCA consortia members (representing 15 institution in eight countries) for future studies were tachycardia (SABA/LABA), adrenal suppression/crisis and growth suppression (corticosteroids), sleep/behaviour disturbances (leukotriene receptor antagonists), and nausea and vomiting (theophylline). Future pharmacogenomic studies in asthma should collect relevant ADR data as well as markers of efficacy.

PMID: 31949291 [PubMed - as supplied by publisher]

SWEDEGENE-a Swedish nation-wide DNA sample collection for pharmacogenomic studies of serious adverse drug reactions.

Pharmacogenomics J. 2020 Jan 17;:

Authors: Hallberg P, Yue QY, Eliasson E, Melhus H, Ås J, Wadelius M

Abstract
SWEDEGENE is a Swedish nation-wide sample collection established to facilitate studies of clinical and genetic risk factors for adverse drug reactions (ADRs). Most cases are recruited among patients reported to the ADR registry at the Swedish Medical Products Agency by health-care professionals. Clinical data are collected both from medical and laboratory records and through interviews using standardized questionnaires. Genome-wide scans and whole-genome sequencing are done, and association studies are conducted using mainly controls from the Swedish TwinGene biobank with data on diagnoses and prescribed drugs. SWEDEGENE was established in 2008 and currently contains DNA and information from about 2550 adults who have experienced specific ADRs, and from 580 drug exposed controls. Results from genome-wide association studies have now been published, and data from whole-genome sequencing are being analyzed. SWEDEGENE has the potential to offer a new means of developing individualized and safe drug therapy through patient pre-treatment screening.

PMID: 31949290 [PubMed - as supplied by publisher]

Medicinal cannabis for psychiatric disorders: a clinically-focused systematic review.

BMC Psychiatry. 2020 Jan 16;20(1):24

Authors: Sarris J, Sinclair J, Karamacoska D, Davidson M, Firth J

Abstract
BACKGROUND: Medicinal cannabis has received increased research attention over recent years due to loosening global regulatory changes. Medicinal cannabis has been reported to have potential efficacy in reducing pain, muscle spasticity, chemotherapy-induced nausea and vomiting, and intractable childhood epilepsy. Yet its potential application in the field of psychiatry is lesser known.
METHODS: The first clinically-focused systematic review on the emerging medical application of cannabis across all major psychiatric disorders was conducted. Current evidence regarding whole plant formulations and plant-derived cannabinoid isolates in mood, anxiety, sleep, psychotic disorders and attention deficit/hyperactivity disorder (ADHD) is discussed; while also detailing clinical prescription considerations (including pharmacogenomics), occupational and public health elements, and future research recommendations. The systematic review of the literature was conducted during 2019, assessing the data from all case studies and clinical trials involving medicinal cannabis or plant-derived isolates for all major psychiatric disorders (neurological conditions and pain were omitted).
RESULTS: The present evidence in the emerging field of cannabinoid therapeutics in psychiatry is nascent, and thereby it is currently premature to recommend cannabinoid-based interventions. Isolated positive studies have, however, revealed tentative support for cannabinoids (namely cannabidiol; CBD) for reducing social anxiety; with mixed (mainly positive) evidence for adjunctive use in schizophrenia. Case studies suggest that medicinal cannabis may be beneficial for improving sleep and post-traumatic stress disorder, however evidence is currently weak. Preliminary research findings indicate no benefit for depression from high delta-9 tetrahydrocannabinol (THC) therapeutics, or for CBD in mania. One isolated study indicates some potential efficacy for an oral cannabinoid/terpene combination in ADHD. Clinical prescriptive consideration involves caution in the use of high-THC formulations (avoidance in youth, and in people with anxiety or psychotic disorders), gradual titration, regular assessment, and caution in cardiovascular and respiratory disorders, pregnancy and breast-feeding.
CONCLUSIONS: There is currently encouraging, albeit embryonic, evidence for medicinal cannabis in the treatment of a range of psychiatric disorders. Supportive findings are emerging for some key isolates, however, clinicians need to be mindful of a range of prescriptive and occupational safety considerations, especially if initiating higher dose THC formulas.

PMID: 31948424 [PubMed - in process]

A large collection of integrated genomically characterized patient-derived xenografts highlighting the heterogeneity of triple-negative breast cancer.

Int J Cancer. 2019 10 01;145(7):1902-1912

Authors: Coussy F, de Koning L, Lavigne M, Bernard V, Ouine B, Boulai A, El Botty R, Dahmani A, Montaudon E, Assayag F, Morisset L, Huguet L, Sourd L, Painsec P, Callens C, Chateau-Joubert S, Servely JL, Larcher T, Reyes C, Girard E, Pierron G, Laurent C, Vacher S, Baulande S, Melaabi S, Vincent-Salomon A, Gentien D, Dieras V, Bieche I, Marangoni E

Abstract
Triple-negative breast cancer (TNBC) represents 10% of all breast cancers and is a very heterogeneous disease. Globally, women with TNBC have a poor prognosis, and the development of effective targeted therapies remains a real challenge. Patient-derived xenografts (PDX) are clinically relevant models that have emerged as important tools for the analysis of drug activity and predictive biomarker discovery. The purpose of this work was to analyze the molecular heterogeneity of a large panel of TNBC PDX (n = 61) in order to test targeted therapies and identify biomarkers of response. At the gene expression level, TNBC PDX represent all of the various TNBC subtypes identified by the Lehmann classification except for immunomodulatory subtype, which is underrepresented in PDX. NGS and copy number data showed a similar diversity of significantly mutated gene and somatic copy number alteration in PDX and the Cancer Genome Atlas TNBC patients. The genes most commonly altered were TP53 and oncogenes and tumor suppressors of the PI3K/AKT/mTOR and MAPK pathways. PDX showed similar morphology and immunohistochemistry markers to those of the original tumors. Efficacy experiments with PI3K and MAPK inhibitor monotherapy or combination therapy showed an antitumor activity in PDX carrying genomic mutations of PIK3CA and NRAS genes. TNBC PDX reproduce the molecular heterogeneity of TNBC patients. This large collection of PDX is a clinically relevant platform for drug testing, biomarker discovery and translational research.

PMID: 30859564 [PubMed - indexed for MEDLINE]

Interaction between IGF2-PI3K axis and cancer-associated-fibroblasts promotes anal squamous carcinogenesis.

Int J Cancer. 2019 10 01;145(7):1852-1859

Authors: Cacheux W, Lièvre A, Richon S, Vacher S, El Alam E, Briaux A, El Botty R, Mariani P, Buecher B, Schnitzler A, Barbazan J, Roman-Roman S, Bièche I, Dangles-Marie V

Abstract
Anal squamous cell carcinoma (ASCC) is a rare tumour, but its incidence is increasing. Standard chemoradiotherapy fails to cure 20% of patients and no targeted therapy is currently approved for recurrent ASCC. The PI3K/Akt/mTOR pathway is frequently altered in this poorly characterised carcinoma. IGF2 was identified here as a key factor in ASCC oncogenesis, as IGF2 was shown to play a crucial role in the PI3K pathway with frequent (~60%) and mutually exclusive genomic alterations in IGF2, IGF1R, PTEN and PIK3CA genes. We also demonstrated that IGF2 expression is mainly due to cancer-associated fibroblasts and that IGF2 secreted by cancer-associated fibroblasts from ASCC samples promotes proliferation of a human ASCC cell line via IGF2 paracrine signalling. Altogether, these results highlight the key role of the IGF2/PI3K axis, and the major role of cancer-associated fibroblasts in tumour growth via IGF2 secretion, suggesting a major role of IGF2/IGF1R inhibitors in ASCC therapies.

PMID: 30714617 [PubMed - indexed for MEDLINE]

Delineating significant genome-wide associations of variants with antipsychotic and antidepressant treatment response: implications for clinical pharmacogenomics.

Hum Genomics. 2020 Jan 15;14(1):4

Authors: Koromina M, Koutsilieri S, Patrinos GP

Abstract
BACKGROUND: Genome-wide association studies (GWAS) have significantly contributed to the association of many clinical conditions and phenotypic characteristics with genomic variants. The majority of these genomic findings have been deposited to the GWAS catalog. So far, findings uncovering associations of single nucleotide polymorphisms (SNPs) with treatment efficacy in mood disorders are encouraging, but not adequate.
METHODS: Statistical, genomic, and literature information was retrieved from EBI's GWAS catalog, while we also searched for potential clinical information/clinical guidelines in well-established pharmacogenomics databases regarding the assessed drug-SNP correlations of the present study.
RESULTS: Here, we provide an overview of significant genome-wide associations of SNPs with the response to commonly prescribed antipsychotics and antidepressants. Up to date, this is the first study providing novel insight in previously reported pharmacogenomics associations for antipsychotic/antidepressant treatment. We also show that although there are published CPIC guidelines for antidepressant agents, as well as the FDA labels include genome-based drug prescription information for both antipsychotic and antidepressant treatments, there are no specific clinical guidelines for the assessed drug-SNP correlations of this study.
CONCLUSIONS: Our present findings suggest that more effort should be implemented towards identifying GWA-significant antipsychotic and antidepressant pharmacogenomics correlations. Moreover, additional functional studies are required in order to characterise the potential role of the assessed SNPs as biomarkers for the response of patients to antipsychotic/antidepressant treatment.

PMID: 31941550 [PubMed - in process]

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]