Effect of recombinant interleukin-2 pretreatment on oral and intravenous digoxin pharmacokinetics and P-glycoprotein activity in mice.

P-glycoprotein (P-gp) is an ATP-dependent efflux membrane transporter involved in many drug pharmacokinetics in humans. Decreasing its expression could enhance the bioavailability of substrates as digoxin. We have recently found that human recombinant interleukin-2 (rIL2) in vivo decreases P-gp expression in intestine and brain of mice and modifies oral digoxin pharmacokinetics. The aim of the study was to evaluate the involvement of bioavailability in the rIL2 pretreatment effect on digoxin pharmacokinetics by comparing oral and i.v. digoxin pharmacokinetics before and after rIL2 pretreatment (10 microg/kg). We also tried to show the possible effect of a low rIL2 dose (1 microg/kg) pretreatment on oral digoxin pharmacokinetics. First, adult Swiss mice received a single oral or i.v. dose of digoxin (0.03 mg/kg). Two weeks later, the same animals were treated by rIL2 i.p. twice a day (10 microg/kg) for 4 days and received digoxin again at day 5. As well, another group received oral digoxin (0.03 mg/kg) with a 1 microg/kg rIL2 pretreatment. Blood was collected after digoxin administration with and without rIL2 pretreatment. Digoxin pharmacokinetics were described by a one-compartment model. The 10 microg/kg rIL2 pretreatment did not modify i.v. digoxin pharmacokinetics, whereas oral digoxin pharmacokinetics were significantly modified by the 10 microg/kg rIL2 pretreatment and not by the 1 microg/kg rIL2 pretreatment. The decrease of P-gp activity, caused by rIL2 (10 microg/kg), increased digoxin bioavailability. An increase in exposure and intracellular level of drugs is expected from rIL2 pretreatment.     

Influence of the punch diameter and curvature on the yield pressure of MCC-compacts during Heckel analysis.

The volume reduction behaviour of powders has been quantified by means of the 'in-die' yield pressure (YP) using Heckel analysis. However, because different YPs are reported for the same material, the experimental conditions influencing this material-constant were investigated. Silicified microcrystalline cellulose was compressed into flat-faced and convex tablets using a compaction simulator instrumented with load and displacement transducers. During compression, upper and lower punch force and displacement data were recorded and corrected for punch deformation. A symmetrical triangle wave compression profile was used and the instantaneous punch velocity was kept constant (5mm/s). Individual tablet height and weight were used for Heckel analysis. The influence of the 'effective compression pressure' (P(EFF)) (ranging from 10 to 350 MPa), punch diameter (PD) (4, 9.5 and 12 mm) and filling depth (FD) (4.5, 7.5 and 10.5mm) on YP was statistically evaluated using Response Surface Modelling software. A quadratic surface response equation, describing the relationship between P(EFF), PD, FD and YP, was proposed for concave (Adj R(2): 0.8424; S.D.: 14.60 MPa) and flat-faced (Adj R(2): 0.8409; S.D.: 4.49 MPa) punches. YP and tensile strength were mainly determined by P(EFF), irrespective of punch curvature. FD and PD had only a minor influence on the YP, although more pronounced for the concave punches. The method used resulted in reproducible P(EFF) and tensile strength values and the flat-faced tablets showed less weight variation. Flat-faced punches are preferred over punches with a concave surface when investigating the volume reduction behaviour of a powder by means of Heckel analysis and the experimental parameters should be reported.     

Feasibility of a randomized controlled trial testing nifedipine vs. placebo for the treatment of preterm labor

AIMS: Nifedipine is believed to be a superior tocolytic agent on the basis of efficacy and side-effect profile, but was never prospectively evaluated in a placebo-controlled randomized clinical trial (RCT). In our study, we sought to identify limitations in participation for a would-be RCT comparing nifedipine to placebo. METHODS: A prospective feasibility study was conducted at Ste-Justine Hospital, a tertiary care center, on women between 24 and 34 weeks' gestation, presenting to the labor and delivery room with obstetrical complaints. Patient information was collected and would-be participants were identified on the basis of pre-established clinical and ultrasound criteria as well as on willingness to participate, as determined by the study research nurse. RESULTS: During a 6-month period, 483 women presenting with signs and symptoms of preterm labor (PTL) were eligible for further evaluation. A total of 321 (66.5%) women were excluded for obstetrical and medical reasons whereas 125 (25.9%) did not meet strict inclusion criteria (cervical length <25 mm or positive fetal fibronectin). When using strict criteria, only 37 women (7.6%) were found to be eligible for study participation. Subject willingness to participate as assessed by the research nurse was 50%. CONCLUSIONS: If adhering to strict inclusion/exclusion criteria, the feasibility of an appropriately sampled RCT testing tocolytic therapy against a placebo would require a large concerted multicenter effort to meet sample size demands.     

Targeting Jab1/CSN5 in nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated head and neck cancer that is most common in eastern Asia. Epstein-Barr virus infection, environmental factors, and genetic susceptibility play important roles in NPC pathogenesis. Jab1/CSN5 is a multifunctional protein that participates in affecting integrin signaling, controlling cell proliferation and apoptosis, and regulating genomic instability and DNA repair. Correlation of Jab1/CSN5 overexpression with poor prognosis for NPC provides evidence that it is involved in the tumorigenic process. In this review, we highlight recent advances in studies of the oncogenic role of Jab1/CSN5 in NPC and its potential as a therapeutic target for this cancer.     

Risky alcohol use among reproductive-age men, not women, in Mae La refugee camp, Thailand, 2009

ABSTRACT: BACKGROUND: Globally, alcohol use contributes to close to 4% of all deaths and is a leading cause of ill health and premature death among men of reproductive age. Problem alcohol use is an unaddressed public health issue among populations displaced by conflict. Assessing the magnitude of the problem and identifying affected groups and risk behaviours is difficult in mobile and unstable populations. METHODS: From 15--28 December 2009 we conducted a simple rapid screening test of risky alcohol use using the single item modified Short Assessment Screening Questionnaire (mSASQ) by all women currently enrolled in the antenatal care clinic in Mae La refugee camp, a long standing displaced setting on the Thai Burma border. Women self- reported and gave a secondary report of their male partners. Gender differences in alcohol use were further explored in semi-structured interviews with camp residents on attitudes, behaviours, and beliefs regarding alcohol and analysed thematically. RESULTS: Of 636 women screened in the antenatal clinic, almost none (0.2%, 95CI 0.0-0.9%) reported risky alcohol use prior to pregnancy, whereas around a quarter (24.4%, 95CI 21.2-27.9%) reported risky alcohol use by their male partners. Interviews with 97 camp residents described strong social controls against women's alcohol use and men's drinking to intoxication, despite a dominant perception that the social context of life in displacement promoted alcohol use and that controls are loosening. CONCLUSIONS: As a stigmatised behaviour, alcohol use is difficult to assess, particularly in the context of highly mobile adult male populations: the simple assessment methods here show that it is feasible to obtain adequate data for the purposes of intervention design. The data suggest that risky drinking is common and normalised among men, but that the population may have been partially protected from rapid rises in problem alcohol use observed in nation-wide data from Thailand. The changing social context contains vulnerabilities that might promote problem alcohol use: further investigation, ongoing monitoring, and development of targeted interventions are warranted.