In vitro and ex vivo evidence for modulation of P-glycoprotein activity by progestins

The well known gender-related differences in drug action may partly be explained by changes in activity and expression of drug metabolising enzymes, but also by modulation of active drug transport systems (e.g. P-glycoprotein, Pgp) by sexual steroids, which is yet not well investigated. Because many women are using hormones (e.g. as oral contraceptives) we investigated the influence of different synthetic progestins on Pgp activity. Pgp inhibition of progesterone, medroxyprogesterone, chlormadinone, cyproterone, levonorgestrel, norethisterone, desogestrel, and norgestimate was measured in vitro in two Pgp over-expressing cell lines (L-MDR1, P388/dx cells) and the corresponding parental cell lines by means of calcein assay, and ex vivo in human peripheral blood mononuclear cells (PBMCs) by rhodamine123 efflux. For most progestins tested, concentrations needed to double baseline fluorescence (f2) in L-MDR1 cells were similar to that of the potent Pgp inhibitor quinidine, whereas levonorgestrel and norethisterone did not reach f2. The results in P388/dx cells essentially confirmed our findings in L-MDR1 cells. Additionally, Pgp inhibitory activity of all progestins tested was also shown ex vivo in PBMCs. The potent Pgp inhibition by several synthetic progestins in vitro and ex vivo suggests that such an interaction might be clinically relevant despite generally low plasma concentrations of progestins. The results may be of particular importance for Pgp substrates, such as protease inhibitors and chemotherapeutic agents, for which intracellular concentrations are critical.     

Correlation between ocular pulse amplitude measured by dynamic contour tonometer and visual field defects

Purpose To investigate the correlation between ocular pulse amplitude and visual field defects in patients with glaucoma, ocular hypertension, and glaucoma suspicion when measured with the Pascal Dynamic Contour Tonometer, and to verify if the ocular pulse amplitude is an independent predictor for visual field parameters. Methods Seventy-seven eyes (42 patients) with glaucoma, ocular hypertension or glaucoma suspicion were examined. Ocular pulse amplitude was measured with the dynamic contour tonometer by one investigator masked to the visual field data. Visual fields were performed within three months of ocular pulse amplitude measurement by the Octopus or Humphrey Field Analyser, and were analysed with Peridata Software. Mean defect, pattern standard deviation (√ Loss Variance) and regression analysis of those parameters (Trend Indices) were correlated with the ocular pulse amplitude for each eye. Results Forty-nine eyes had glaucoma, 14 had ocular hypertension, and 14 were glaucoma suspects. The mean follow-up was 46.5 (range 6–96) months. There was a significant correlation between OPA and MD and OPA and PSD, even after correction for IOP (and diagnostic group and eye): the estimated slope equals 2.68 (S.E. = 0.82, p = 0.003) and −0.86 (S.E. = 0.33, p = 0.014), respectively. There was even a weak correlation between OPA and the evolution of MD (dB/year). The slope estimate for OPA equals 0.070 (S.E. = 0.033), p = 0.037. However, after correction for IOP (and diagnostic group and eye), the strength of the relationship is reduced and the evidence disappears: the slope estimate for OPA now equals 0.039 (S.E. = 0.041), p = 0.34. There is no evidence for an association between OPA and the evolution of Trend-PSD. Conclusion A small ocular pulse amplitude, as measured with a dynamic contour tonometer, is correlated with moderate to severe glaucomatous visual field loss and might be a risk factor for the development of glaucomatous visual field defects.     

The effects of a hearing education program on recreational noise exposure,attitudes and beliefs toward noise,hearing loss,and hearing protector devices in young adults

Excessive recreational noise exposure in young adults might result in noise-induced hearing loss (NIHL) and tinnitus. Inducing behavioral change in young adults is one of the aims of a hearing conservation program (HCP). The goal of the current study was to evaluate the effect of a hearing education program after 6 months in young adults in relation to knowledge regarding their individual hearing status. The results of a questionnaire regarding the weekly equivalent recreational noise exposure, attitudes and beliefs toward noise, and hearing loss and hearing protector devices (HPDs) were compared between both sessions. Seventy-eight young adults completed the questionnaire concerning recreational noise exposure, youth attitude to noise scale (YANS), and beliefs about hearing protection and hearing loss (BAHPHL). Their hearing status was evaluated based on admittance measures, audiometry, transient-evoked otoacoustic emissions (TEOAEs), and distortion-product otoacoustic emissions (DPOAEs). The main analysis consisted of a mixed model analysis of variance with dependent variables of either the noise exposure or the scores on (subscales of) YANS and BAHPHL. The independent variables were hearing status and session one versus session two. There was a significant decrease in recreational noise exposure and several (sub) scales of YANS and BAHPHL between both the sessions. This behavioral change resulted in a more frequent use of HPDs in 12% of the participants. However, the behavioral change was not completely related to the knowledge of young adults’ individual hearing status. To prevent hearing damage in young people, investing in HCPs is necessary, apart from regulating sound levels and its compliance at various leisure-time activities. Also, the long-term effect of HCPs and their most cost-efficient repetition rates should be further investigated.     

Estimating marginal causal effects in a secondary analysis of case‐control data

When an initial case‐control study is performed, data can be used in a secondary analysis to evaluate the effect of the case‐defining event on later outcomes. In this paper, we study the example in which the role of the event is changed from a response variable to a treatment of interest. If the aim is to estimate marginal effects, such as average effects in the population, the sampling scheme needs to be adjusted for. We study estimators of the average effect of the treatment in a secondary analysis of matched and unmatched case‐control data where the probability of being a case is known. For a general class of estimators, we show the components of the bias resulting from ignoring the sampling scheme and demonstrate a design‐weighted matching estimator of the average causal effect. In simulations, the finite sample properties of the design‐weighted matching estimator are studied. Using a Swedish diabetes incidence register with a matched case‐control design, we study the effect of childhood onset diabetes on the use of antidepressant medication as an adult. Copyright © 2017 John Wiley & Sons, Ltd.     

Expression pattern of gastrointestinal selenoproteins— targets for selenium supplementation

There is experimental and epidemiological evidence for an association between low selenium levels and gastrointestinal cancer incidence, prevalence, and mortality. To identify targets for selenium supplementation in the human digestive tract, we examined mRNA expression of various selenocysteine‐containing proteins in normal mucosa biopsy specimens. Tissue samples from the esophagus and from different sites of the stomach, small bowel, and colon were obtained during endoscopies of the upper and lower gastrointestinal tract. Northern blot analyses revealed a lack of cytosolic glutathione peroxidase mRNA but a differential mRNA expression pattern of gastrointestinal and plasma glutathione peroxidase, selenoprotein P, and thioredoxin reductase. Glutathione peroxidase and thioredoxin reducíase activities were detected in the mucosa of all biopsies, but the differential pattern did not reflect the differential mRNA steady‐state levels. In addition to gastrointestinal glutathione peroxidase, which was found to play a role in colon cancer resistance, we identified further gastrointestinal selenoproteins, which may be involved in gastrointestinal cell defense and cell differentiation.     

Geriatric Rehabilitation: Elderly Clients' Experiences of a Pre-discharge Occupational Therapy Group Programme

This study describes how elderly people, temporarily living in a pre-discharge community rehabilitation centre, may experience participation in an in-patient occupational therapy programme built around group activities. The group activity programme was comprised of five sessions, each focusing on a theme chosen to encourage reflection and mutual sharing of experiences and support. Data were collected through interviews with each of the three participants immediately after each of the five group sessions. The resultant 15 interviews were analysed by adopting a Grounded Theory approach. The results show that the ways in which the participants experienced participating in the group activity programme can be described from two distinct core categories: experiences of activation and experiences of transformation . The category of activation emerged from their experiences of a creative force whilst engaged in performing the activities and from their discovery that the group was a good place for learning . Engagement in the group activities also seemed to bring about a transformation in the participants in that their experiences triggered reflection and adaptation , which contributed to a change in attitude and a personal synthesis where their new discoveries were internalized. The study shows the potential a group activity programme in occupational therapy has in triggering an adaptational and reflective process within elderly people facing discharge from hospital. Hence, group activity interventions in occupational therapy are suggested as one possible way to support the elderly person in the discharge process from hospital to the home.     

Studying psychoactive substance use in injured patients: Does exclusion of late arriving patients bias the results?

BackgroundMost studies of the prevalence of psychoactive substances in injured emergency department patients have excluded those who arrive more than 6 h after injury. This may cause a selection bias. The aim of this study was: (1) to describe the characteristics of patients who arrive more than 6 h after injury, compared to patients who arrive sooner (2) to examine whether self-report can add to the assessment of alcohol use when the patient is assessed more than 6 h after injury.MethodsBlood sample analysis and self-report data were used to assess the prevalence of psychoactive substances in injured patients admitted to an emergency department within 48 h of injury (n = 1611). Discriminant function analysis was used to assess group differences.ResultsThe patients who arrived more than 6 h after injury differed significantly from those who arrived earlier in several respects. They more often screened positive for hypnotics; they were older, they were more likely to have had a fall and they were more often injured at home and at night. Self reported use of alcohol showed good consistency with blood sample screening within 6 h of injury and could therefore be used to assess alcohol use more than 6 h after injury.ConclusionsPatients who arrive more than 6 h after injury differ significantly from those who arrive earlier. Future studies on the prevalence of psychoactive substances in emergency departments could expand the inclusion window.     

Preservative-free versus preserved latanoprost eye drops in patients with open-angle glaucoma or ocular hypertension

Objective: This study compared the efficacy, safety, and pharmacokinetics of a preservative-free latanoprost formulation to an established, benzalkonium chloride (BAK) containing formulation for the treatment of open-angle glaucoma or ocular hypertension.

Methods: This was a phase II, randomized, cross-over, investigator-masked, multi-center, pilot study (NCT01494753). A total of 30 untreated adult patients (aged ≥18 years) with primary open angle glaucoma, pseudo-exfoliative glaucoma, pigmentary glaucoma, or ocular hypertension received either preservative-free or preserved latanoprost once daily in both eyes for 6 weeks, before crossing over to receive the other treatment. Efficacy (intraocular pressure [IOP] at 8 am, midday, 4?pm and 8?pm, and global efficacy assessment by investigator), safety (adverse events, ocular symptoms and global tolerance, slit lamp examination, funduscopy, visual field examination, visual acuity, and heart rate), and pharmacokinetics were assessed at Days 0, 42, and 84.

Results: Both treatments resulted in a reduction in IOP that was similar for the preservative-free and the preserved formulation at all time points. Similarly, the overall diurnal reduction was similar in both groups (6.3?mmHg [27.9% reduction] and 6.4?mmHg [28.1% reduction] for preserved and preservative-free latanoprost, respectively). There were no differences in global efficacy assessment or in the safety and tolerance of each treatment. Systemic concentrations of latanoprost were very low; AUC_0–30 and C_max were lower and t_max was longer for preservative-free latanoprost.

Conclusions: Preservative-free latanoprost showed similar efficacy at all time points compared to BAK preservative containing formulation, with no difference in tolerance, allowing progression to phase III clinical development.     

Objective assessment of nonadherence and unknown co-medication in hospitalized patients

Purpose

The intake of medications (drugs) without the knowledge of the treating physician (unknown co-medication) and nonadherence strongly influence drug safety. The aim of our study was to objectively assess unknown co-medication and nonadherence in hospitalized patients by screening urine for a large number of drugs using highly sensitive full scan gas chromatograpy/mass spectrometry (GC/MS). Secondary objectives were to determine the relationship of co-medication and nonadherence to the number of drugs prescribed and to compare history-taking by a pharmacist versus a physician.

Methods

In 152 patients, the drug histories taken by physicians, patients’ self-reported adherence, and information compiled during as many as three structured interviews conducted by a trained pharmacist on days 1–2, 3–4, and 7–11 of the hospital stay were compared with the GC/MS results from urine samples collected after each interview.

Results

In the interviews performed by the pharmacist, 235 additional drugs were identified that were not documented in the chart. Of all the drugs indicated in any interview, 16.9% were identified only by the physician, 24.1% only by the pharmacist, and 59% by both. Overall, in 78% of the patients at least one additional drug was identified by urine screening. The findings suggest overall nonadherence to at least one drug in 13.0% of patients on admission and in 23.3% of patients at any time during hospitalization. Nonadherence was less frequent for critical dose drugs and correlated with the number of prescribed drugs.

Conclusions

The drug history among hospitalized patients is often incomplete, and nonadherence and unknown co-medication are alarmingly frequent. This lack of knowledge might impact the overall success of drug therapies in the hospital setting.