Afatinib is an oral, irreversible ErbB family blocker that covalently binds to the kinase domains of epidermal growth factor receptor (EGFR), human EGFRs (HER) 2, and HER4, resulting in irreversible ...inhibition of tyrosine kinase autophosphorylation. Studies in healthy volunteers and patients with advanced solid tumours have shown that once-daily afatinib has time-independent pharmacokinetic characteristics. Maximum plasma concentrations of afatinib are reached approximately 2–5 h after oral administration and thereafter decline, at least bi-exponentially. Food reduces total exposure to afatinib. Over the clinical dose range of 20–50 mg, afatinib exposure increases slightly more than dose proportional. Afatinib metabolism is minimal, with unchanged drug predominantly excreted in the faeces and approximately 5 % in urine. Apart from the parent drug afatinib, the major circulation species in human plasma are the covalently bound adducts to plasma protein. The effective elimination half-life is approximately 37 h, consistent with an accumulation of drug exposure by 2.5- to 3.4-fold based on area under the plasma concentration–time curve (AUC) after multiple dosing. The pharmacokinetic profile of afatinib is consistent across a range of patient populations. Age, ethnicity, smoking status and hepatic function had no influence on afatinib pharmacokinetics, while females and patients with low body weight had increased exposure to afatinib. Renal function is correlated with afatinib exposure, but, as for sex and body weight, the effect size for patients with severe renal impairment (approximately 50 % increase in AUC) is only mildly relative to the extent of unexplained interpatient variability in afatinib exposure. Afatinib has a low potential as a victim or perpetrator of drug–drug interactions, especially with cytochrome P450-modulating agents. However, concomitant treatment with potent inhibitors or inducers of the P-glycoprotein transporter can affect the pharmacokinetics of afatinib. At a dose of 50 mg, afatinib does not have proarrhythmic potential.
The Caco-2 model is a well-accepted in vitro model for the estimation of fraction absorbed in human intestine. Due to the lack of cytochrome P450 3A4 (CYP3A4) activities, Caco-2 model is not suitable ...for the investigation of intestinal first-pass metabolism. The purpose of this study is to evaluate a new human intestine model, EpiIntestinal microtissues, as a tool for the prediction of oral absorption and metabolism of drugs in human intestine. The activities of relevant drug transporters and drug metabolizing enzymes, including MDR1 P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), CYP3A4, CYP2J2, UDP-glucuronosyltransferases (UGT), carboxylesterases (CES), etc., were detected in functional assays with selective substrates and inhibitors. Compared to Caco-2, EpiIntestinal microtissues proved to be a more holistic model for the investigation of drug absorption and metabolism in human gastrointestinal tract.
Intramyocellular (IMCL), extramyocellular lipid (EMCL), and vitamin D deficiency are associated with muscle metabolic dysfunction. This study compared the change in IMCL:EMCL following the combined ...treatment of vitamin D and aerobic training (DAT) compared with vitamin D (D), aerobic training (AT), and control (CTL). Male and female subjects aged 60-80 years with a BMI ranging from 18.5-34.9 and vitamin D status of ≤32 ng/mL (25(OH)D) were recruited to randomized, prospective clinical trial double-blinded for supplement with a 2 × 2 factorial design. Cholecalciferol (Vitamin D
) (10,000 IU × 5 days/week) or placebo was provided for 13 weeks and treadmill aerobic training during week 13. Gastrocnemius IMCL and EMCL were measured with magnetic resonance spectroscopy (MRS) and MRI. Hybrid near-infrared diffuse correlation spectroscopy measured hemodynamics. Group differences in IMCL were observed when controlling for baseline IMCL (
= 0.049). DAT was the only group to reduce IMCL from baseline, while a mean increase was observed in all other groups combined (
= 0.008). IMCL reduction and the corresponding increase in rVO
at study end (
= 0.011) were unique to DAT. Vitamin D, when combined with exercise, may potentiate the metabolic benefits of exercise by reducing IMCL and increasing tissue-level VO
in healthy, older adults.
Optimal chemotherapy with minimal toxicity is the main determinant of complete remission in patients with newly diagnosed hematological malignancies. Acute organ dysfunctions may impair the patient's ...ability to receive optimal chemotherapy.
To compare 6-month complete remission rates in patients with and without acute kidney injury (AKI), we collected prospective data on 200 patients with newly diagnosed high-grade malignancies (non-Hodgkin lymphoma, 53.5%; acute myeloid leukemia, 29%; acute lymphoblastic leukemia, 11.5%; and Hodgkin disease, 6%).
According to RIFLE criteria, 137 (68.5%) patients had AKI. Five causes of AKI accounted for 91.4% of cases: hypoperfusion, tumor lysis syndrome, tubular necrosis, nephrotoxic agents, and hemophagocytic lymphohistiocytosis. Half of the AKI patients received renal replacement therapy and 14.6% received suboptimal chemotherapy. AKI was associated with a lower 6-month complete remission rate (39.4% vs. 68.3%, P<0.01) and a higher mortality rate (47.4% vs. 30.2%, P<0.01) than patients without AKI. By multivariate analysis, independent determinants of 6-month complete remission were older age, poor performance status, number of organ dysfunctions, and AKI.
AKI is common in patients with newly diagnosed high-grade malignancies and is associated with lower complete remission rates and higher mortality.
Purpose
Noninvasive ventilation (NIV) had proven benefits in clinical trials that included selected patients admitted to highly skilled centers. Whether these benefits apply to every patient and in ...everyday practice deserves appraisal. The aim of the study was to assess the use and outcomes of NIV over the last 15 years.
Methods
Multicenter database study of critically ill patients who required ventilatory support for acute respiratory failure between 1997 and 2011. The impact of first-line NIV on 60-day mortality was evaluated using a marginal structural model. Follow-up was censored on day 60.
Results
Of 3,163 patients, 1,232 (39 %) received NIV. Over the study period, first-line NIV increased from 29 to 42 %, and NIV success rates increased from 69 to 84 %. NIV decreased 60-day mortality adjusted hazard ratio (aHR), 0.75; 95 % confidence interval (95 % CI), 0.68–0.83;
P
< 0.0001. This protective effect was observed in patients with acute-on-chronic respiratory failure (aHR, 0.71; 95 % CI, 0.57–0.90;
P
= 0.004), but not in patients with cardiogenic pulmonary edema (aHR, 0.85; 95 % CI, 0.70–1.03;
P
= 0.10) or in patients with hypoxemic ARF, either immunocompetent (aHR, 1.18; 95 % CI, 0.87–1.59;
P
= 0.30) or immunocompromised (aHR, 0.89; 95 % CI, 0.70–1.13;
P
= 0.35). NIV failure was an independent time-dependent risk factor for mortality (aHR, 4.2; 95 % CI, 2.8–6.2;
P
< 0.0001).
Conclusions
The use of NIV increased steadily over the study period. First-line NIV was associated with better 60-day survival and fewer ICU-acquired infections compared to first-line intubation. Survival benefits from NIV occurred only in patients with acute-on-chronic respiratory failure and immunocompromised patients.
Abstract Background and objectives Doppler-based renal resistive index (RI) might help in distinguishing transient from persistent acute kidney injury (AKI). The main objective of these systematic ...review and meta-analysis was to investigate the diagnostic performance of RI in predicting short-term reversibility of AKI. Study design A systematic review of the literature was performed. Relevant studies were identified in Pubmed and Cochrane databases covering the years 1985 to 2013 and reviewed independently by 3 authors. Renal transplant recipients were excluded from this analysis. The summary estimates were computed using a random-effects model based on the DerSimonian and Lair meta-analytic method. Results Among the 154 unique articles identified, 9 studies were included. Of the 176 patients in these studies with elevated RI or pulsatility index, 146 (83%) had a persistent AKI vs 44 (16%) of the 273 patients with normal values. Elevated RI or pulsatility index was associated with an increased risk of persistent AKI (odds ratio, 29.85; 95% confidence interval CI, 8.73-102.16; P < .00001) with significant heterogeneity ( I2 = 75.0%, P < .0001). The pooled sensitivity and specificity were 0.83 (95% CI, 0.77-0.88) and 0.84 (95% CI, 0.79-0.88). The summary positive and negative likelihood ratios were 4.9 (95% CI, 2.44-9.87) and 0.21 (95% CI, 0.11-0.41). Conclusion These results suggest that an elevated RI may be a predictor of persistent AKI in critically ill patients. Further studies are warranted, however, to clarify the exact test performance given the marked heterogeneity among the included studies.
Vitamin D has been connected with increased intramyocellular lipid (IMCL) and has also been shown to increase mitochondrial function and insulin sensitivity. Evidence suggests that perilipin 2 ...(PLIN2), a perilipin protein upregulated with calcitriol treatment, may be integral to managing increased IMCL capacity and lipid oxidation in skeletal muscle. Therefore, we hypothesized that PLIN2 is required for vitamin D induced IMCL accumulation and increased mitochondrial oxidative function. To address this hypothesis, we treated C2C12 myotubes with 100 nM calcitriol (the active form of vitamin D) and/or PLIN2 siRNA in a four group design and analyzed markers of IMCL accumulation and metabolism using qRT-PCR, cytochemistry, and oxygen consumption assay. Expression of PLIN2, but not PLIN3 or PLIN5 mRNA was increased with calcitriol, and PLIN2 induction was prevented with siRNA knockdown without compensation by other perilipins. PLIN2 knockdown did not appear to prevent lipid accumulation. Calcitriol treatment increased mRNA expression of triglyceride synthesizing genes DGAT1 and DGAT2 and also lipolytic genes ATGL and CGI-58. PLIN2 knockdown decreased the expression of CGI-58 and CPT1, and was required for calcitriol-induced upregulation of DGAT2. Calcitriol increased oxygen consumption rate while PLIN2 knockdown decreased oxygen consumption rate. PLIN2 was required for a calcitriol-induced increase in oxygen consumption driven by mitochondrial complex II. We conclude that calcitriol increases mitochondrial function in myotubes and that this increase is at least in part mediated by PLIN2.
Cancer cells typically experience higher oxidative stress than normal cells, such that elevating pro-oxidant levels can trigger cancer cell death. Although pre-exposure to mild oxidative agents will ...sensitize cancer cells to radiation, this pre-exposure may also activate the adaptive stress defense system in normal cells. Ascorbic acid is a prototype redox modulator that when infused intravenously appears to kill cancers without injury to normal tissues; however, the mechanisms involved remain elusive. In this study, we show how ascorbic acid kills cancer cells and sensitizes prostate cancer to radiation therapy while also conferring protection upon normal prostate epithelial cells against radiation-induced injury. We found that the NF-κB transcription factor RelB is a pivotal determinant in the differential radiosensitization effects of ascorbic acid in prostate cancer cells and normal prostate epithelial cells. Mechanistically, high reactive oxygen species concentrations suppress RelB in cancer cells. RelB suppression decreases expression of the sirtuin SIRT3 and the powerful antioxidant MnSOD, which in turn increases oxidative and metabolic stresses in prostate cancer cells. In contrast, ascorbic acid enhances RelB expression in normal cells, improving antioxidant and metabolic defenses against radiation injury. In addition to showing how RelB mediates the differential effects of ascorbic acid on cancer and normal tissue radiosensitivities, our work also provides a proof of concept for the existence of redox modulators that can improve the efficacy of radiotherapy while protecting against normal tissue injury in cancer settings.
.
Vitamin D reduces myocellular insulin resistance, but the effects of vitamin D on intramyocellular lipid (IMCL) partitioning are unknown. The purpose of this study was to understand how calcitriol, ...the active vitamin D metabolite, affects insulin sensitivity and lipid partitioning in skeletal muscle cells. C2C12 myotubes were treated with calcitriol (100 nM) or vehicle control for 96 h. Insulin-stimulated Akt phosphorylation (Thr 308) was determined by western blot. Intramyocellular triacylglycerol (IMTG), diacylglycerol (DAG), and ceramide content were measured by LC/MS. IMTG partitioning and lipid droplet accumulation were assessed by oil red O. Expression of genes involved in lipid droplet packaging and lipolysis were measured by RT-PCR. Compared to vehicle-treated myotubes, calcitriol augmented insulin-stimulated pAkt. Calcitriol increased total ceramides and DAG in a subspecies-specific manner. Specifically, calcitriol preferentially increased ceramide 24:1 (1.78 fold) and di-18:0 DAG (46.89 fold). Calcitriol increased total IMTG area as assessed by oil red O, but decreased the proportion of lipid within myotubes. Calcitriol increased mRNA content of genes involved in lipid droplet packaging (perilipin 2; PLIN 2, 2.07 fold) and lipolysis (comparative gene identification-58; CGI-58 and adipose triglyceride lipase; ATGL, ~ 1.80 fold). Calcitriol alters myocellular lipid partitioning and lipid droplet packaging which may favor lipid turnover and partially explain improvements in insulin sensitivity.
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