Navigating Transporter Sciences in Pharmacokinetics Characterization Using Extended Clearance Classification System (ECCS).

Drug Metab Dispos. 2018 Mar 01;:

Authors: El-Kattan AF, Varma MVS

Abstract
Membrane transporters play an important role in the absorption, distribution, clearance and elimination (ADCE) of the drugs. Supported by the pharmacokinetics data in human, several transporters including organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)2, multidrug and toxin extrusion proteins (MATEs), P-glycoprotein and breast cancer resistance protein (BCRP) are suggested to be of clinical relevance. An early understanding of transporters role in the drug disposition and clearance allows reliable prediction/evaluation of the pharmacokinetic changes due to drug-drug interactions (DDIs) or genetic polymorphisms. We recently proposed extended clearance classification system (ECCS) based on simple drug properties (i.e., ionization permeability and molecular weight) to predict predominant clearance mechanism. According to this framework, systemic clearance of class 1B and 3B drugs is likely determined by the OATP-mediated hepatic uptake. Class 3A, 4 and certain class 3B drugs are predominantly cleared by renal, wherein, OAT1, OAT3, OCT2 and MATEs could contribute to their active renal secretion. Intestinal efflux and uptake transporters largely influence the oral pharmacokinetics of class 3A, 3B and 4 drugs. We discuss the paradigm of applying ECCS framework in mapping the role of clinically relevant drug transporters in early discovery and development; and thereby, implementing the right strategy to allow optimization of drug exposure and evaluation of clinical risk due to DDIs and pharmacogenomics.

PMID: 29496721 [PubMed - as supplied by publisher]

Lung Disease and Genomics.

AACN Adv Crit Care. 2018;29(1):74-83

Authors: Wysocki K

Abstract
Research and application of genomic medicine in lung disease during the past century has clarified our understanding and focus on specific phenotypes, helping clinicians tailor treatment for individual patients. Cystic fibrosis and lung cancer have been researched extensively; specific genotypes have been instrumental in precision medicine to treat these lung diseases. Asthma and chronic obstructive pulmonary disease are more complex and heterogeneous in their pathogenesis, genotypic profile, and phenotypic expression, making treatment more difficult with increasing disease severity. This article focuses on the evolving state of the science of precision medicine in lung cancer, chronic obstructive pulmonary disease, asthma, and cystic fibrosis. The body of knowledge in lung disease is growing related to pharmacogenomics, clinical guidelines, genome editing, and approaches to genomic health that will guide clinical treatment options, reduce risk, and promote health.

PMID: 29496715 [PubMed - in process]

Pharmacogenomics in Critical Care.

AACN Adv Crit Care. 2018;29(1):36-42

Authors: Cheek D, Howington L

Abstract
Since the successful completion of the Human Genome Project in 2003, extensive genomic research has continued to alter pathophysiology at the molecular level. This research includes investigation of the specific receptors and metabolizing enzymes in drug pharmacodynamics and pharmacokinetics, specifically the cytochrome P450 system located primarily in the liver. In this article, pharmacogenomics and the role of the cytochrome P450 system in metabolism of various drugs are discussed. Specifically, drugs that are used in the critical care setting and are of clinical significance to the bedside critical care nurse are examined.

PMID: 29496712 [PubMed - in process]

Genomics and Precision Medicine: Implications for Critical Care.

AACN Adv Crit Care. 2018;29(1):28-35

Authors: Kessler C

Abstract
A new paradigm for disease diagnosis and treatment is emerging that will bring about changes in health care delivery in and out of the hospital setting. Over the past several decades, genomic medicine has been one of the fastest growing fields in acute and chronic health care. This quick growth has created a lag in genomics knowledge and preparation among nurses and health care providers. Genomic medicine may lead to more precise evaluation, diagnosis, and management of selected acute care conditions. This article reviews the current state of genetic and genomics science and looks at the expanding field of genomic medicine's integration into precision medicine. The aim of this article is to raise awareness and spark further inquiry to the remarkable field of genomics and precision medicine.

PMID: 29496711 [PubMed - in process]

CDX2 prognostic value in stage II/III resected colon cancer is related to CMS classification.

Ann Oncol. 2017 May 01;28(5):1032-1035

Authors: Pilati C, Taieb J, Balogoun R, Marisa L, de Reyniès A, Laurent-Puig P

Abstract
Background: Caudal-type homeobox transcription factor 2 (CDX2) is involved in colon cancer (CC) oncogenesis and has been proposed as a prognostic biomarker in patients with stage II or III CC.
Patients and methods: We analyzed CDX2 expression in a series of 469 CC typed for the new international consensus molecular subtype (CMS) classification, and we confirmed results in a series of 90 CC.
Results: Here, we show that lack of CDX2 expression is only present in the mesenchymal subgroup (CMS4) and in MSI-immune tumors (CMS1) and not in CMS2 and CMS3 colon cancer. Although CDX2 expression was a globally independent prognostic factor, loss of CDX2 expression is not associated with a worse prognosis in the CMS1 group, but is highly prognostic in CMS4 patients for both relapse free and overall survival. Similarly, lack of CDX2 expression was a bad prognostic factor in MSS patients, but not in MSI.
Conclusions: Our work suggests that combination of the consensual CMS classification and lack of CDX2 expression could be a useful marker to identify CMS4/CDX2-negative patients with a very poor prognosis.

PMID: 28328000 [PubMed - indexed for MEDLINE]

ANTIBIOTIC RESISTANCE EVOLUTION OF PSEUDOMONAS AERUGINOSA IN CYSTIC FIBROSIS PATIENTS (2010-2013).

Clin Respir J. 2018 Mar 02;:

Authors: Lucca F, Guarnieri M, Ros M, Muffato G, Rigoli R, Da Dalt L

Abstract
INTRODUCTION: Pseudomonas aeruginosa is the predominant pathogen responsible of chronic colonization of the airways in Cystic Fibrosis patients. There are few European data about antibiotic susceptibility evolution of Pseudomonas aeruginosa in Cystic Fibrosis patients.
OBJECTIVES: The aim of this study is to evaluate the evolution of antibiotic resistance in the period 2010-2013 in Cystic Fibrosis patients chronically colonized by Pseudomonas aeruginosa and to highlight the characteristics of this evolution in patients younger than 20 years.
METHODS: Clinical and microbiological data were extracted from two electronic databases and analyzed. Antibiotic resistance was defined according to EUCAST for levofloxacin, ciprofloxacin, meropenem, amikacin, ceftazidime. The between-group comparison was drawn with the Chi-square test for proportions, with the T-test for unpaired samples for normally distributed data and with Mann-Whitney test for non-normally distributed data. Significancy was defined by p<0.05.
RESULTS: Fifty-seven Cystic Fibrosis patients, including thirteen subjects aged less than 20 years, were enrolled. Pseudomonas aeruginosa antibiotic sensitivity decreased significantly for fluoroquinolones, mainly in patients aged< 20 years, while it increased for amikacin and colistin. The analysis of Minimum Inhibitory Concentration confirmed these trends. In pediatric patients treated with more than 3 antibiotic cycles per year, greater resistance was found, except for amikacin and colistin.
CONCLUSION: An evolution in Pseudomonas aeruginosa antibiotic resistances is observed in the four-years period studied. Responsible and informed use of antibiotics is mandatory in Cystic Fibrosis. This article is protected by copyright. All rights reserved.

PMID: 29498795 [PubMed - as supplied by publisher]

Molecular typing of Burkholderia cepacia complex isolated from patients attending an Italian Cystic Fibrosis Centre.

New Microbiol. 2018 Mar 02;41(1)

Authors: Teri A, Sottotetti S, Biffi A, Girelli D, D'Accico M, Arghittu M, Colombo C, Corti F, Pizzamiglio G, Cariani L

Abstract
Bacteria from the Burkholderia cepacia complex (Bcc) are capable of causing severe infections in patients with cystic fibrosis (CF). Bcc infection is often extremely difficult to treat due to its intrinsic resistance to multiple antibiotics. In addition, it seems to speed up the decline of lung function and is considered a contraindication for lung transplantation in CF. This study investigates the species of the Bcc strains recovered from chronically infected CF subjects by means of: isolation, identification methods and complete recA nucleotide sequences of 151 samples. Molecular typing showed that B. cenocepacia III is the dominant strain found in the group of subjects being treated at the Milan CF Centre (Italy) and that the infection is chronically maintained by the same species. Defining species by means of molecular analysis yields important information for the clinician in order to establish the most appropriate therapy and implement correct measures for prevention of transmission among CF subjects.

PMID: 29498745 [PubMed - as supplied by publisher]

Behaviour of Bdellovibrio bacteriovorus in the presence of Gram-positive Staphylococcus aureus.

New Microbiol. 2018 Mar 02;41(1)

Authors: Pantanella F, Iebba V, Mura F, Dini L, Totino V, Neroni B, Bonfiglio G, Maria T, Passariello C, Schippa S

Abstract
The present study aimed to characterize the behavior of Bdellovibrio bacteriovorus in the presence of Staphylococcus aureus. B. bacteriovorus was co-cultured with S. aureus or Pseudomonas aeruginosa or Streptococcus mutans, in planktonic and sessile conditions. Co-cultures were studied by Field-Emission Scanning Electron Microscopy (FESEM), Scanning Transmission Electron Microscopy (STEM), turbidimetry, quantitative PCR (qPCR), and sequencing of gene Bd0108 of B. bacteriovorus. Results indicated that B. bacteriovorus comparably inhibited planktonic growth of P. aeruginosa and S. aureus, but not of S. mutans. FESEM and STEM showed that B. bacteriovorus interacts with S. aureus affecting its cell wall and membrane. Sequencing of gene Bd0108 did not reveal any of the mutations that can arise from hit locus. Although some Gram-negative species are reported to be B. bacteriovorus prey, it seems that in case of nutrient deficiency this predatory bacterium can also take advantage of some Gram-positive species. B. bacteriovorus behaviour in the presence of S. aureus is relevant for its possible therapeutic use in several pathologies, like cystic fibrosis in which S. aureus and P. aeruginosa frequently coexist as infectious agents.

PMID: 29498744 [PubMed - as supplied by publisher]

Achoo, achis, ATCHIN! Vaccine you….

Eur Respir J. 2018 Mar;51(3):

Authors: Froes F, Blasi F, Torres A

PMID: 29496787 [PubMed - in process]

Lung Disease and Genomics.

AACN Adv Crit Care. 2018;29(1):74-83

Authors: Wysocki K

Abstract
Research and application of genomic medicine in lung disease during the past century has clarified our understanding and focus on specific phenotypes, helping clinicians tailor treatment for individual patients. Cystic fibrosis and lung cancer have been researched extensively; specific genotypes have been instrumental in precision medicine to treat these lung diseases. Asthma and chronic obstructive pulmonary disease are more complex and heterogeneous in their pathogenesis, genotypic profile, and phenotypic expression, making treatment more difficult with increasing disease severity. This article focuses on the evolving state of the science of precision medicine in lung cancer, chronic obstructive pulmonary disease, asthma, and cystic fibrosis. The body of knowledge in lung disease is growing related to pharmacogenomics, clinical guidelines, genome editing, and approaches to genomic health that will guide clinical treatment options, reduce risk, and promote health.

PMID: 29496715 [PubMed - in process]

β- Adrenoceptors activate hepatic glutathione efflux through an unreported pathway.

Arch Biochem Biophys. 2018 Feb 26;:

Authors: Matuz-Mares D, Hernández-Vázquez A, Riveros-Rosas H, Guinzberg R, Quesada-López T, Cárabez-Trejo A, Mora O, Piña E

Abstract
The physiological regulation of hepatic glutathione efflux by catecholamines is poorly understood. The purpose of this work was to review the role of adrenergic receptors (AR) on total glutathione (GT) efflux in rat liver. Two models were used: isolated hepatocytes and perfused livers. In hepatocytes 10 μM adrenaline (Adr), but not isoproterenol (Iso) a β-AR agonist, or phenylephrine (Phe) an α1-AR agonist, (in a Krebs-Henseleit Buffer (KHB) enriched with Ca2+ and some aminoacids) increased in 13% GT efflux. In livers perfused with KHB, Adr or Iso at 1 μmolar doses (but not Phe) stimulated 11-fold initial velocity of GT release, but only during the first 2 min of perfusion. This immediate response progressively disappeared during the following 15 min of perfusion. A second phase of GT efflux, observed between 2 and 14 min of perfusion, mimics the one reported earlier in isolated hepatocytes. The ED50 for Adr and Iso activation are in the range of 320 nM and 10 nM, respectively. Iso-mediated GT release requires Ca2+ to work, and was prevented by H89, glibenclamide, cystic fibrosis transmembrane regulator (CFTR) antibodies, and a direct CFTR inhibitor. This short-lived GT release system is associated to PKA activation and probably operates through CFTR.

PMID: 29496543 [PubMed - as supplied by publisher]

Potential associations between atazanavir exposure and clinical outcome: a pharmacokinetic sub-study from the MODAt randomized trial.

New Microbiol. 2018 Mar 02;41(1)

Authors: Colella E, Cattaneo D, Galli L, Baldelli S, Clementi E, Galli M, Lazzarin A, Castagna A, Rusconi S, Spagnuolo V

Abstract
The 96-week results of the Monotherapy Once a Day with Atazanavir/r (MODAt) study [NCT01511809] showed an inferior virological efficacy of atazanavir (ATV)/ritonavir monotherapy versus triple therapy, which was promptly retrieved by the reintroduction of nucleoside/nucleotide inhibitors of reverse transcriptase [N(n)RTIs]. We aimed to identify potential relationships between ATV exposure and clinical outcome in HIV-1 subjects treated with ATV/ritonavir monotherapy [ATV/r 300/100mg] versus ATV/ritonavir triple therapy [ATV/r 300/100mg+2NRTIs]. A chromatographic method coupled with tandem mass spectrometry was applied to analyze ATV plasma concentrations in a pharmacokinetic sub-study from the MODAt trial. Mixed linear models were used to examine the ATV plasma concentration trend during follow-up and to assess the association between ATV plasma concentrations trajectories with the study arm or the occurrence of treatment failure or drug-related adverse events or the grading of baseline total bilirubin (<3 vs ≥3). The analyses were performed using SAS Software, release 9.4 (SAS Institute, Cary, NC, USA). Overall, ATV plasma Ctrough concentration did not vary during follow-up (slope: +0.75 ng/mL/week, 95%CI: -0.97 to 2.47, p=0.387); trajectories did not differ between study arms 2 (p=0.527). The unadjusted model-based means (95%CI) of ATV Ctrough during follow-up were 835 (95%CI: 657-1012) ng/ml in the ATV/r monotherapy arm as compared to 911 (95%CI: 740-1082) ng/mL in the ATV/r triple therapy arm (p=0.621). Mean ATV Ctrough was similar in subjects with or without adverse events (AEs). Subjects treated with ATV/r monotherapy showed significantly higher ATV concentrations as compared to subjects without adverse events or treated with ATV/r triple therapy. ATV concentrations were associated with the grading of baseline total bilirubin and the occurrence of drug-related AEs but not with HCV infection. Our findings showed a lack of association between ATV concentrations and treatment failure both in ATV/r monotherapy and triple therapy. Conversely, these data emphasized that ATV concentrations are associated with the development of side-effects in both subjects treated with ATV/r monotherapy and subjects treated with ATV/r triple therapy.

PMID: 29498742 [PubMed - as supplied by publisher]

Comparison of efficacy of haloperidol and olanzapine in the treatment of delirium.

Indian J Psychiatry. 2017 Oct-Dec;59(4):451-456

Authors: Jain R, Arun P, Sidana A, Sachdev A

Abstract
Objective: Till date, typical antipsychotic haloperidol is the treatment of choice for delirium. But, due to higher side effects with haloperidol, newer atypical antipsychotics (e.g., olanzapine) are increasingly being used in the treatment of delirious patients. The aim of the current research was to study the efficacy and tolerability of haloperidol and olanzapine in the treatment of delirium.
Materials and Methods: This was an open-label, randomized controlled study carried out in a tertiary care hospital at Chandigarh, India. A total of 100 patients admitted in medicine, surgery, and orthopedic wards and diagnosed as having delirium on Confusion Assessment Method scale were included in the study. Patients were given either haloperidol (1-4 mg/day either orally or by nasogastric tube) or olanzapine (2.5-10 mg/day either orally or by nasogastric tube). Severity of delirium and pattern of symptom improvement were assessed by Memorial Delirium Assessment Scale (MDAS). Extrapyramidal side effects were assessed by Simpson-Angus Scale.
Results: There was an improvement in delirium severity in both groups with treatment. Mean daily dose of haloperidol and olanzapine used per patient was 2.10 and 5.49 mg, respectively, and the mean duration of treatment in olanzapine group and haloperidol group was 3.57 days and 3.37 days, respectively. There was no significant difference in the mean duration of treatment in both groups. At the end of study period, the MDAS scores in olanzapine and haloperidol groups were 8.43 and 8.00, respectively, and the difference was not significant statistically with P = 0.765. Five patients experienced drug-related mild side effects.
Conclusion: Low-dose haloperidol and olanzapine were equally efficacious and well tolerated in delirium.

PMID: 29497187 [PubMed - in process]

Finding balance: Optimizing medication prescribing in older patients.

Cleve Clin J Med. 2018 02;85(2):136-137

Authors: Sponsler KC, Mixon AS

PMID: 29425084 [PubMed - indexed for MEDLINE]

Risk Factors for Chemotherapy-Related Toxicity and Adverse Events in Elderly Thai Cancer Patients: A Prospective Study.

Oncology. 2018;94(3):149-160

Authors: Phaibulvatanapong E, Srinonprasert V, Ithimakin S

Abstract
OBJECTIVES: To assess factors predisposing to severe chemotherapy-related toxicity and adverse events (AEs) and dose modification in aging cancer patients.
METHODS: Cancer patients aged ≥70 years scheduled to receive the first cycle of a new chemotherapy regimen were enrolled. On the day of starting chemotherapy, demographic data, performance status (PS), and geriatric parameters were recorded. AEs and chemotherapy modification were recorded. Quality of life (QOL) was assessed at baseline and 3 months after starting chemotherapy or at the end of chemotherapy.
RESULTS: We included 151 patients (mean age, 76.4 years) with gastrointestinal (47%), lung (24%), breast (9%), or genitourinary (6%) cancer. All-grade and severe AEs occurred in 83 and 42% of patients, respectively; 51.6% of patients required chemotherapy modification due to toxicities. A higher incidence of severe AEs (71% vs. 39%, p = 0.01) and poorer QOL was found in patients with PS 2 than in those with PS 0-1. Patients with PS 2 or who received palliative-intent chemotherapy or had multiple comorbidities were more likely to discontinue chemotherapy because of toxicity.
CONCLUSIONS: PS remains a key predictor of chemotherapy-related toxicity in elderly patients. PS 2 was correlated with higher incidence of severe AEs, premature treatment discontinuation, and worsening QOL after treatment.

PMID: 29212082 [PubMed - indexed for MEDLINE]

Incidence, course, and management of toxicities associated with cobimetinib in combination with vemurafenib in the coBRIM study.

Ann Oncol. 2017 05 01;28(5):1137-1144

Authors: Dréno B, Ribas A, Larkin J, Ascierto PA, Hauschild A, Thomas L, Grob JJ, Koralek DO, Rooney I, Hsu JJ, McKenna EF, McArthur GA

Abstract
Background: In the coBRIM phase III trial, the addition of cobimetinib, an MEK inhibitor, to vemurafenib, a BRAF inhibitor, significantly improved progression-free survival [hazard ratio (HR), 0.58; P < 0.0001] and overall survival (HR, 0.70; P = 0.005) in advanced BRAF-mutated melanoma. Here, we report on the incidence, course, and management of key adverse events (AEs) in the coBRIM study.
Patients and methods: Patients were randomly assigned 1:1 to receive vemurafenib (960 mg twice a day) and either cobimetinib (60 mg once a day, 21 days on/7 days off) or placebo. In addition to standard safety evaluations, patients underwent regular ophthalmic, cardiac, and dermatologic surveillance examinations.
Results: Of 495 patients recruited to the study, 493 patients received treatment and constituted the safety population (cobimetinib combined with vemurafenib, 247; vemurafenib, 246). At data cut-off (30 September 2015), median follow-up was 18.5 months. Nearly every patient experienced an AE. In patients who received cobimetinib combined with vemurafenib, the frequency of grade ≥3 AEs was higher than in patients who received vemurafenib alone (75% versus 61%). Most AEs, including grade ≥3 AEs, occurred within the first treatment cycle. After the first cycle (28 days), the incidence of common AEs (rash, diarrhoea, photosensitivity, elevated creatine phosphokinase, serous retinopathy, pyrexia, and liver laboratory abnormalities) decreased substantially over time. Most AEs were managed conservatively by supportive care measures, dose modifications of study treatment, and, occasionally, permanent treatment discontinuation.
Conclusions: These data indicate that most AEs arising from treatment with cobimetinib combined with vemurafenib generally occur early in the treatment course, are mild or moderate and are manageable by patient monitoring, dose modification and supportive care.
ClinicalTrials.gov: NCT01689519.

PMID: 28444112 [PubMed - indexed for MEDLINE]

Phase II study of idelalisib, a selective inhibitor of PI3Kδ, for relapsed/refractory classical Hodgkin lymphoma.

Ann Oncol. 2017 May 01;28(5):1057-1063

Authors: Gopal AK, Fanale MA, Moskowitz CH, Shustov AR, Mitra S, Ye W, Younes A, Moskowitz AJ

Abstract
Background: The phosphatidylinositol-3-kinase delta (PI3Kδ) inhibitor idelalisib has been shown to block downstream intracellular signaling, reduce the production of prosurvival chemokines and induce apoptosis in classical Hodgkin lymphoma (HL) cell lines. It has also been shown to inhibit regulatory T cells and myeloid-derived suppressor cells in other tumor models. We hypothesized that inhibiting PI3Kδ would have both direct and indirect antitumor effects by directly targeting the malignant cells as well as modulating the inflammatory microenvironment. We tested this hypothesis in a phase II study.
Patients and methods: We enrolled 25 patients with relapsed/refractory HL with a median age of 42 years and who had previously received a median of five therapies including 18 (72%) with failed autologous stem cell transplant, 23 (92%) with failed brentuximab vedotin, and 11 (44%) with prior radiation therapy. Idelalisib was administered at 150 mg two times daily; an increase to 300 mg two times daily was permitted at the time of disease progression.
Results: The overall response rate to idelalisib therapy was 20% (95% confidence interval: 6.8%, 40.7%) with a median time to response of 2.0 months. Seventeen patients (68%) experienced reduction in target lesions with one complete remission and four partial remissions. The median duration of response was 8.4 months and median progression-free survival was 2.3 months. The most common grade ≥3 adverse event was elevation of alanine aminotransferase (two patients, 8%). Diarrhea/colitis was seen in three patients and was grade 1-2. There was one adverse event leading to death (hypoxia).
Conclusions: Idelalisib was tolerable and had modest single-agent activity in heavily pretreated patients with HL. Rational combinations with other novel agents may improve response rate and duration of response.
Clinical trial registration: ClinicalTrials.gov # NCT01393106.

PMID: 28327905 [PubMed - indexed for MEDLINE]

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