A single nucleotide polymorphism of IL6-receptor is associated with response to tocilizumab in rheumatoid arthritis patients.

Pharmacogenomics J. 2019 Jan 16;:

Authors: Luxembourger C, Ruyssen-Witrand A, Ladhari C, Rittore C, Degboe Y, Maillefert JF, Gaudin P, Marotte H, Wendling D, Jorgensen C, Cantagrel A, Constantin A, Nigon D, Touitou I, Gottenberg JE, Pers YM

Abstract
Biological disease-modifying anti-rheumatic drugs (bDMARDs) have changed care of patients with rheumatoid arthritis (RA). However, bDMARDs are costly, can lead to serious infections, and induce a sustained remission in only 30% of RA patients. In this study, we sought to determine if the clinical response to treatment with Tocilizumab (TCZ), an IL-6 inhibitor, varied with genetic background. The efficacy of TCZ was assessed using the European League Against Rheumatism (EULAR) response criteria, measured after 3 months of treatment in two samples of French RA patients (TOCI and ROC studies). Single nucleotide polymorphisms (SNPs) in 21 candidate genes were genotyped using KasPar method (LGC-genomics, UK) and then analyzed to determine their contribution to variation in the response to treatment. One hundred twenty-three patients in the TOCI group (79.8%) and 48 patients in the ROC group (80%) experienced good or moderate EULAR response. The clinical response to treatment was associated with SNP genotype in the gene IL6R, with patients with the homozygous AA-genotype for rs12083537 (IL6R) showing a significantly better response than homozygous or heterozygous patients with the G allele [TOCI: 87.5% of responders for AA genotype vs. 72.2% for AG or GG genotype (p = 0.018); ROC patients: 89.2% of responders for AA genotype vs. 65.2% for AG or GG genotype, p = 0.044]. A meta-analysis combining data from the two cohorts confirmed the lower response rate in patients carrying a copy of the G allele (OR (95% CI) = 0.35 (0.16-0.61), p = 0.001). No association was found with any of the other SNPs tested.

PMID: 30647443 [PubMed - as supplied by publisher]

Gabapentin as add-on to morphine for severe neuropathic or mixed pain in children from age 3 months to 18 years - evaluation of the safety, pharmacokinetics, and efficacy of a new gabapentin liquid formulation: study protocol for a randomized controlled trial.

Trials. 2019 Jan 15;20(1):49

Authors: de Leeuw TG, Mangiarini L, Lundin R, Kaguelidou F, van der Zanden T, Pasqua OD, Tibboel D, Ceci A, de Wildt SN, GAPP consortium

Abstract
BACKGROUND: Gabapentin has shown efficacy in the treatment of chronic neuropathic or mixed pain in adults. Although pediatric pain specialists have extensive experience with gabapentin for the treatment of neuropathic pain, its use is off-label. Its efficacy and safety in this context have never been shown. The aim of this trial is to compare gabapentin with placebo as add-on to morphine for the treatment of severe chronic mixed or neuropathic pain in children. This trial is part of the European Union Seventh Framework Programme project Gabapentin in Paediatric Pain (GAPP) to develop a pediatric use marketing authorization for a new gabapentin suspension.
METHODS/DESIGN: The GAPP-2 study is a randomized, double-blind, placebo-controlled, multicenter superiority phase II study in children with severe chronic neuropathic or mixed pain. Its primary objective is to evaluate the efficacy of a gabapentin liquid formulation as adjunctive therapy to morphine. Sixty-six eligible children 3 months to 18 years of age with severe pain (pain scores ≥ 7), stratified in three age groups, will be randomized to receive gabapentin (to an accumulating dose of 45 to 63 mg/kg/day, dependent on age) or placebo, both in addition to morphine, for 12 weeks. Randomization will be preceded by a short washout period, and treatment will be initiated by a titration period of 3 weeks. After the treatment period, medication will be tapered during 4 weeks. The primary endpoint is the average pain scores in the two treatment groups (average of two measures each day for 3 days before the end-of-study visit [V10] assessed by age-appropriate pain scales (Face, Legs, Activity, Cry, Consolability scale; Faces Pain Scale-Revised; Numeric Rating Scale). Secondary outcomes include percentage responders to treatment (subjects with 30% reduction in pain scale), number of episodes of breakthrough pain, number of rescue interventions, number of pain-free days, participant dropouts, quality of life (Pediatric Quality of Life Inventory), and acceptability of treatment. Outcomes will be measured at the end-of-study visit after 12 weeks of treatment at the optimal gabapentin dose. Groups will be compared on an intention-to-treat basis.
DISCUSSION: We hope to provide evidence that the combination of morphine and gabapentin will provide better analgesia than morphine alone and will be safe. We also aim to obtain confirmation of the recommended pediatric dose.
TRIAL REGISTRATION: EudractCT, 2014-004897-40 . Registered on 7 September 2017. ClinicalTrials.gov, NCT03275012 . Registered on 7 September 2017.

PMID: 30646965 [PubMed - in process]

Colorectal Cancer Biomarkers in the Era of Personalized Medicine.

J Pers Med. 2019 Jan 14;9(1):

Authors: Patel JN, Fong MK, Jagosky M

Abstract
The 5-year survival probability for patients with metastatic colorectal cancer has not drastically changed over the last several years, nor has the backbone chemotherapy in first-line disease. Nevertheless, newer targeted therapies and immunotherapies have been approved primarily in the refractory setting, which appears to benefit a small proportion of patients. Until recently, rat sarcoma (RAS) mutations remained the only genomic biomarker to assist with therapy selection in metastatic colorectal cancer. Next generation sequencing has unveiled many more potentially powerful predictive genomic markers of therapy response. Importantly, there are also clinical and physiologic predictive or prognostic biomarkers, such as tumor sidedness. Variations in germline pharmacogenomic biomarkers have demonstrated usefulness in determining response or risk of toxicity, which can be critical in defining dose intensity. This review outlines such biomarkers and summarizes their clinical implications on the treatment of colorectal cancer. It is critical that clinicians understand which biomarkers are clinically validated for use in practice and how to act on such test results.

PMID: 30646508 [PubMed]

Transcription Factor Activities Enhance Markers of Drug Sensitivity in Cancer.

Cancer Res. 2018 02 01;78(3):769-780

Authors: Garcia-Alonso L, Iorio F, Matchan A, Fonseca N, Jaaks P, Peat G, Pignatelli M, Falcone F, Benes CH, Dunham I, Bignell G, McDade SS, Garnett MJ, Saez-Rodriguez J

Abstract
Transcriptional dysregulation induced by aberrant transcription factors (TF) is a key feature of cancer, but its global influence on drug sensitivity has not been examined. Here, we infer the transcriptional activity of 127 TFs through analysis of RNA-seq gene expression data newly generated for 448 cancer cell lines, combined with publicly available datasets to survey a total of 1,056 cancer cell lines and 9,250 primary tumors. Predicted TF activities are supported by their agreement with independent shRNA essentiality profiles and homozygous gene deletions, and recapitulate mutant-specific mechanisms of transcriptional dysregulation in cancer. By analyzing cell line responses to 265 compounds, we uncovered numerous TFs whose activity interacts with anticancer drugs. Importantly, combining existing pharmacogenomic markers with TF activities often improves the stratification of cell lines in response to drug treatment. Our results, which can be queried freely at dorothea.opentargets.io, offer a broad foundation for discovering opportunities to refine personalized cancer therapies.Significance: Systematic analysis of transcriptional dysregulation in cancer cell lines and patient tumor specimens offers a publicly searchable foundation to discover new opportunities to refine personalized cancer therapies. Cancer Res; 78(3); 769-80. ©2017 AACR.

PMID: 29229604 [PubMed - indexed for MEDLINE]

Pharmacogenomics of amlodipine and hydrochlorothiazide therapy and the quest for improved control of hypertension: a mini review.

Heart Fail Rev. 2019 Jan 15;:

Authors: Johnson R, Dludla P, Mabhida S, Benjeddou M, Louw J, February F

Abstract
Blood pressure (BP) is a complex trait that is regulated by multiple physiological pathways and include but is not limited to extracellular fluid volume homeostasis, cardiac contractility, and vascular tone through renal, neural, or endocrine systems. Uncontrolled hypertension (HTN) has been associated with an increased mortality risk. Therefore, understanding the genetics that underpins and influence BP regulation will have a major impact on public health. Moreover, uncontrolled HTN has been linked to inter-individual variation in the drugs' response and this has been associated with an individual's genetics architecture. However, the identification of candidate genes that underpin the genetic basis of HTN remains a major challenge. To date, few variants associated with inter-individual BP regulation have been identified and replicated. Research in this field has accelerated over the past 5 years as a direct result of on-going genome-wide association studies (GWAS) and the progress in the identification of rare gene variants and mutations, epigenetic markers, and the regulatory pathways involved in the pathophysiology of BP. In this review we describe and enhance our current understanding of how genetic variants account for the observed variability in BP response in patients on first-line antihypertensive drugs, amlodipine and hydrochlorothiazide.

PMID: 30645721 [PubMed - as supplied by publisher]

Genetic determinants of acute asthma therapy response in children with moderate-to-severe asthma exacerbations.

Pediatr Pulmonol. 2019 Jan 15;:

Authors: Tse SM, Krajinovic M, Chauhan BF, Zemek R, Gravel J, Chalut D, Poonai N, Quach C, Laberge S, Ducharme FM, DOORWAY research group of the Pediatric Emergency Research in Canada (PERC) network

Abstract
BACKGROUND: We documented inter-individual variability in the response to acute asthma therapy in children, attributed in part to five clinical factors (oxygen saturation, asthma severity score, virus detection, fever, symptoms between exacerbations; DOORWAY study). The contribution of genetic determinants of failure of acute asthma management have not been elucidated.
OBJECTIVE: We aim to determine single nucleotide polymorphisms (SNP) associated with emergency department (ED) management failure in children.
METHODS: A prospective cohort of 591 Caucasian children aged 1-17 years with moderate-to-severe asthma managed with standardized protocol were included. We examined 53 SNPs previously associated with asthma development, phenotypes, or bronchodilator or corticosteroids response. Associations between SNPs and management failure (hospitalization, active asthma management ≥8 h in ED, or a return visit within 72 h for one of two previous criteria) were examined using logistic regression, adjusting for the five clinical predictors of management failure.
RESULTS: Four-hundred ninety-one subjects had complete clinical data and usable DNA samples. While controlling for clinical determinants, rs295137 in SPATS2L (OR = 1.77, 95%CI: 1.17, 2.68) was significantly associated with increased odds of ED management failure. Two SNPs in IL33 were associated with decreased odds of ED management failure: rs7037276 (OR = 0.55, 95%CI: 0.33, 0.90), and rs1342326 (OR = 0.52, 95%CI: 0.32, 0.86). The addition of these three SNPs to the clinical predictors significantly improved the model's predictive performance (P < 0.0004).
CONCLUSION: Three SNPs were significantly associated with ED management failure in addition to clinical predictors, contributing to inter-individual variability. None has been previously associated with treatment response to acute asthma management.

PMID: 30644648 [PubMed - as supplied by publisher]

Immunoglobulin deposition on biomolecule corona determines complement opsonization efficiency of preclinical and clinical nanoparticles.

Nat Nanotechnol. 2019 Jan 14;:

Authors: Vu VP, Gifford GB, Chen F, Benasutti H, Wang G, Groman EV, Scheinman R, Saba L, Moghimi SM, Simberg D

Abstract
Deposition of complement factors (opsonization) on nanoparticles may promote clearance from the blood by macrophages and trigger proinflammatory responses, but the mechanisms regulating the efficiency of complement activation are poorly understood. We previously demonstrated that opsonization of superparamagnetic iron oxide (SPIO) nanoworms with the third complement protein (C3) was dependent on the biomolecule corona of the nanoparticles. Here we show that natural antibodies play a critical role in C3 opsonization of SPIO nanoworms and a range of clinically approved nanopharmaceuticals. The dependency of C3 opsonization on immunoglobulin binding is almost universal and is observed regardless of the complement activation pathway. Only a few surface-bound immunoglobulin molecules are needed to trigger complement activation and opsonization. Although the total amount of plasma proteins adsorbed on nanoparticles does not determine C3 deposition efficiency, the biomolecule corona per se enhances immunoglobulin binding to all nanoparticle types. We therefore show that natural antibodies represent a link between biomolecule corona and C3 opsonization, and may determine individual complement responses to nanomedicines.

PMID: 30643271 [PubMed - as supplied by publisher]

[Research progress of copper transporter 1 in platinum-based chemotherapy].

Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2018 Dec 28;43(12):1376-1379

Authors: Ouyang Q, Liu Y, Liu Y

Abstract
Platinum drugs are widely used in the treatment of various solid tumors, but their resistance to platinum is the most significant obstacle to successful treatment. Copper transporter 1 (CTR1) is the specific transporter for copper, and it mainly locates at the plasma membrane and plays a role in pumping copper into the cell. CTR1 is also the major platinum influx transporter and plays a key role in platinum resistance. The expression, polymorphism, and degradation of CTR1 affect platinum resistance in tumors. Therefore, CTR1 may be a potential predictive biomarker of platinum resistance and a therapeutic target for overcoming platinum resistance.

PMID: 30643056 [PubMed - in process]

Mitochondria-targeted antioxidant delivery for precise treatment of myocardial ischemia-reperfusion injurythrough a multistage continuous targeted strategy.

Nanomedicine. 2019 Jan 09;:

Authors: Cheng Y, Liu DZ, Zhang CX, Cui H, Liu M, Zhang BL, Mei QB, Lu ZF, Zhou SY

Abstract
Efficient delivery of antioxidant drugs into mitochondria of ischemic cardiomyocytes where reactive oxygen species largely induced is a major challenge for precise treatment of myocardial ischemia-reperfusion injury. Herein, we report a smart dual-shell polymeric nanoparticle, MCTD-NPs, which utilizes multistage continuous targeted strategy to deliver reactive oxygen species scavenger specifically to mitochondria of ischemic cardiomyocytes upon systemic administration. In vitro experiments indicated that the intracellular uptake of MCTD-NPs was specifically enhanced in hypoxia reoxygenation injured H9c2 cells. MCTD-NPs selectively delivered resveratrol to mitochondria of hypoxia reoxygenation injured H9c2 cells. In addition, MCTD-NPs increased the viability of H/R injured H9c2 cell through eliminating mitochondrial ROS, decreasing mPTP opening and blocking mitochondria-dependent apoptotic pathway. In vivo experiments revealed that MCTD-NPs increased the distribution of resveratrol in the ischemic myocardium and subsequently reduced infarct size in MI/RI rats. These results demonstrated a novel platform for specific delivery of antioxidant to mitochondria to treat MI/RI.

PMID: 30639669 [PubMed - as supplied by publisher]

Identification of canine cytochrome P-450s (CYPs) metabolizing the tramadol (+)-M1 and (+)-M2 metabolites to the tramadol (+)-M5 metabolite in dog liver microsomes.

J Vet Pharmacol Ther. 2018 Dec;41(6):815-824

Authors: Perez Jimenez TE, Mealey KL, Schnider D, Grubb TL, Greene SA, Court MH

Abstract
We previously showed that (+)-tramadol is metabolized in dog liver to (+)-M1 exclusively by CYP2D15 and to (+)-M2 by multiple CYPs, but primarily CYP2B11. However, (+)-M1 and (+)-M2 are further metabolized in dogs to (+)-M5, which is the major metabolite found in dog plasma and urine. In this study, we identified canine CYPs involved in metabolizing (+)-M1 and (+)-M2 using recombinant enzymes, untreated dog liver microsomes (DLMs), inhibitor-treated DLMs, and DLMs from CYP inducer-treated dogs. A canine P-glycoprotein expressing cell line was also used to evaluate whether (+)-tramadol, (+)-M1, (+)-M2, or (+)-M5 are substrates of canine P-glycoprotein, thereby limiting their distribution into the central nervous system. (+)-M5 was largely formed from (+)-M1 by recombinant CYP2C21 with minor contributions from CYP2C41 and CYP2B11. (+)-M5 formation in DLMs from (+)-M1 was potently inhibited by sulfaphenazole (CYP2C inhibitor) and chloramphenicol (CYP2B11 inhibitor) and was greatly increased in DLMs from phenobarbital-treated dogs. (+)-M5 was formed from (+)-M2 predominantly by CYP2D15. (+)-M5 formation from (+)-M1 in DLMs was potently inhibited by quinidine (CYP2D inhibitor) but had only a minor impact from all CYP inducers tested. Intrinsic clearance estimates showed over 50 times higher values for (+)-M5 formation from (+)-M2 compared with (+)-M1 in DLMs. This was largely attributed to the higher enzyme affinity (lower Km) for (+)-M2 compared with (+)-M1 as substrate. (+)-tramadol, (+)-M1, (+)-M2, or (+)-M5 were not p-glycoprotein substrates. This study provides a clearer picture of the role of individual CYPs in the complex metabolism of tramadol in dogs.

PMID: 30113702 [PubMed - indexed for MEDLINE]

How can the 'omics' revolution can change primary care.

Fam Pract. 2017 04 01;34(2):125-126

Authors: Dawes M

PMID: 28158337 [PubMed - indexed for MEDLINE]

Response to Gammal et al.

Genet Med. 2019 Jan 11;:

Authors: Vassy JL, Stone A, Callaghan JT, Mendes M, Meyer LJ, Pratt VM, Przygodzki RM, Scheuner MT, Wang-Rodriguez J, Schichman SA, VHA Clinical Pharmacogenetics Subcommittee

Abstract

PMID: 30635623 [PubMed - as supplied by publisher]

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Genetic variation of kinases and activation of nucleotide analog reverse transcriptase inhibitor tenofovir.

Pharmacogenomics. 2019 Jan 10;:

Authors: Hamlin AN, Tillotson J, Bumpus NN

Abstract
As antiretroviral therapy has become more accessible across the world and coformulations have improved patient compliance; the morbidity and mortality of HIV/AIDS has decreased. However, there is still a substantial gap in knowledge regarding the impact of genetic variation on the metabolism of and response to some of the most commonly prescribed antiretrovirals, including the nucleotide reverse transcriptase inhibitor tenofovir. While it has been scientifically established that tenofovir must be activated to be efficacious against HIV, the enzymes responsible for this activation have not been well characterized. The purpose of this review is to summarize and clarify the scientific knowledge regarding the enzymes that phosphorylate and activate this clinically important drug.

PMID: 30628547 [PubMed - as supplied by publisher]

Validation of a clinical pharmacogenetic model to predict methotrexate nonresponse in rheumatoid arthritis patients.

Pharmacogenomics. 2019 Jan 10;:

Authors: Eektimmerman F, Allaart CF, Hazes JM, den Broeder AA, Fransen J, Swen JJ, Guchelaar HJ

Abstract
AIM: To study the performance of a clinical pharmacogenetic model for the prediction of nonresponse in rheumatoid arthritis (RA) patients treated with methotrexate (MTX) in combination with other synthetic or biologic disease-modifying anti-rheumatic drugs . This prediction model includes gender, smoking status, rheumatoid factor positivity and four genetic variants in AMPD1 (rs17602729), ATIC (rs2372536), ITPA (rs1127354) and MTHFD1 (rs17850560).
METHODS:  A total of 314 RA patients from three Dutch studies were retrospectively included. Eligible patients were adults diagnosed with RA and had a treatment duration with MTX and follow-up for at least two study evaluation visits. Prediction model risk scores at the first and second evaluation were calculated and compared with the actual nonresponse (disease activity score >2.4). Regression and receiver operating characteristic curve analyses of the prediction model were performed. Also, the sensitivity, specificity and the positive and negative predictive values (PPV and NPV) were determined.
RESULTS: The receiver operating characteristic area under the curve was 75% at first and 70% after second evaluation. At the second evaluation, prediction nonresponse had a sensitivity of 67% (CI: 54-78%), specificity of 69% (CI: 60-77%), PPV of 52% (CI: 45-60%) and NPV of 80% (CI: 73-85%).
CONCLUSIONS: This study demonstrates that the clinical pharmacogenetic model has an inadequate performance for the prediction of nonresponse to MTX in RA patients treated with combination therapies.

PMID: 30628539 [PubMed - as supplied by publisher]

Cost-effectiveness analysis of UGT1A1*6/*28 genotyping for preventing FOLFIRI-induced severe neutropenia in Chinese colorectal cancer patients.

Pharmacogenomics. 2019 Jan 10;:

Authors: Wei X, Cai J, Sun H, Li N, Xu C, Zhang G, Sui Y, Zhuang J, Zheng B

Abstract
AIM: To assess the cost-effectiveness of UGT1A1*6/*28 genotyping compared with no genotyping or no dose adjustment before irinotecan administration in China.
MATERIALS & METHODS: A decision tree model was developed to evaluate costs and health outcomes represented as quality-adjusted life years gained. Model inputs for the frequency of genotypes, the probability of neutropenia under FOLFIRI chemotherapy and direct costs and utilities were obtained from published sources. One-way sensitivity analyses were performed.
RESULTS: The strategy of genotyping with dose reduction dominated all remaining strategies. Compared with the strategies of no genotyping and genotyping with unchanged dose, it resulted in only marginal quality-adjusted life year increases (0.0011 and 0.0012) but a cost reduction of $651.12 and $805.22 per patient, respectively. One-way sensitivity analyses revealed that the model was relatively robust.
CONCLUSION: UGT1A1*6/*28 genotyping was cost saving for Chinese colorectal cancer patients.

PMID: 30628534 [PubMed - as supplied by publisher]

What Does it Take to Make Model-Informed Precision Dosing Common Practice? Report from the 1st Asian Symposium on Precision Dosing.

AAPS J. 2019 Jan 09;21(2):17

Authors: Polasek TM, Rostami-Hodjegan A, Yim DS, Jamei M, Lee H, Kimko H, Kim JK, Nguyen PTT, Darwich AS, Shin JG

Abstract
Model-informed precision dosing (MIPD) is modeling and simulation in healthcare to predict the drug dose for a given patient based on their individual characteristics that is most likely to improve efficacy and/or lower toxicity in comparison to traditional dosing. This paper describes the background and status of MIPD and the activities at the 1st Asian Symposium of Precision Dosing. The theme of the meeting was the question, "What does it take to make MIPD common practice?" Formal presentations highlighted the distinction between genetic and non-genetic sources of variability in drug exposure and response, the use of modeling and simulation as decision support tools, and the facilitators to MIPD implementation. A panel discussion addressed the types of models used for MIPD, how the pharmaceutical industry views MIPD, ways to upscale MIPD beyond academic hospital centers, and the essential role of healthcare professional education as a way to progress. The meeting concluded with an ongoing commitment to use MIPD to improve patient care.

PMID: 30627939 [PubMed - in process]

Sorafenib N-Oxide Is an Inhibitor of Human Hepatic CYP3A4.

AAPS J. 2019 Jan 09;21(2):15

Authors: Ghassabian S, Gillani TB, Rawling T, Crettol S, Nair PC, Murray M

Abstract
The multi-kinase inhibitor sorafenib (SOR) is clinically important in the treatment of hepatocellular and renal cancers and undergoes CYP3A4-dependent oxidation in liver to the pharmacologically active N-oxide metabolite (SNO). There have been reports that kinase inhibitors such as SOR may precipitate pharmacokinetic interactions with coadministered drugs that compete for CYP3A4-mediated biotransformation, but these occur non-uniformly in patients. Clinical evidence also indicates that SNO accumulates in serum of some patients during prolonged SOR therapy. In this study undertaken in hepatic microsomes from individual donors, we assessed the possibility that SNO might contribute to pharmacokinetic interactions mediated by SOR. Enzyme kinetics of CYP3A4-mediated midazolam 1'-hydroxylation in individual human hepatic microsomes were analyzed by non-linear regression and appropriate replots. Thus, SNO and SOR were linear-mixed inhibitors of microsomal CYP3A4 activity (Kis 15 ± 4 and 33 ± 14 μM, respectively). To assess these findings, further molecular docking studies of SOR and SNO with the 1TQN crystal structure of CYP3A4 were undertaken. SNO elicited a larger number of interactions with key amino acid residues located in substrate recognition sequences of the enzyme. In the optimal docking pose, the N-oxide moiety of SNO was also found to interact directly with the heme moiety of CYP3A4. These findings suggest that SNO could contribute to pharmacokinetic interactions involving SOR, perhaps in individuals who produce high circulating concentrations of the metabolite.

PMID: 30627802 [PubMed - in process]

A novel scaffold for EGFR inhibition: Introducing N-(3-(3-phenylureido)quinoxalin-6-yl) acrylamide derivatives.

Sci Rep. 2019 Jan 09;9(1):14

Authors: do Amaral DN, Lategahn J, Fokoue HH, da Silva EMB, Sant'Anna CMR, Rauh D, Barreiro EJ, Laufer S, Lima LM

Abstract
Clinical data acquired over the last decade on non-small cell lung cancer (NSCLC) treatment with small molecular weight Epidermal Growth Factor Receptor (EGFR) inhibitors have shown significant influence of EGFR point mutations and in-frame deletions on clinical efficacy. Identification of small molecules capable of inhibiting the clinically relevant EGFR mutant forms is desirable, and novel chemical scaffolds might provide knowledge regarding selectivity among EGFR forms and shed light on new strategies to overcome current clinical limitations. Design, synthesis, docking studies and in vitro evaluation of N-(3-(3-phenylureido)quinoxalin-6-yl) acrylamide derivatives (7a-m) against EGFR mutant forms are described. Compounds 7h and 7l were biochemically active in the nanomolar range against EGFRwt and EGFRL858R. Molecular docking and reaction enthalpy calculations have shown the influence of the combination of reversible and covalent binding modes with EGFR on the inhibitory activity. The inhibitory profile of 7h against a panel of patient-derived tumor cell lines was established, demonstrating selective growth inhibition of EGFR related cells at 10 μM among a panel of 30 cell lines derived from colon, melanoma, breast, bladder, kidney, prostate, pancreas and ovary tumors.

PMID: 30626888 [PubMed - in process]

Sex, drugs, and heart failure: a sex-sensitive review of the evidence base behind current heart failure clinical guidelines.

ESC Heart Fail. 2018 10;5(5):745-754

Authors: Levinsson A, Dubé MP, Tardif JC, de Denus S

Abstract
Heart failure (HF) is a complex disease, almost as common in women as in men. Nonetheless, HF clinical presentation, prognosis, and aetiology vary by sex. This review summarizes the current state of sex-sensitive issues related to HF drugs included in treatment guidelines and suggests future directions for improved care. Heart failure presentation differs between female and male patients: females more often show with hypertensive aetiology and the preserved ejection fraction phenotype, while men more often show ischaemic aetiology and the reduced ejection fraction phenotype. Yet the HF clinical guidelines in Europe, the United States, and Canada do not reflect the sexual dimorphism. Further, in randomized clinical trials of HF medication, women are largely underrepresented, typically consisting of ≥70% men. Given the knowledge that some adverse drug reactions, such as torsade de pointes and angiotensin-converting enzyme inhibitor-induced cough, occur more frequently in women, we emphasize the need to test medications thoroughly in both sexes and explore sexual dimorphisms. To better represent all of the targeted patient population and provide better care for all, two kinds of change must come about: recruitment methods to randomized clinical trial samples need to evolve and the participation needs to seem more attractive to women.

PMID: 29916560 [PubMed - indexed for MEDLINE]