Midazolam microdosing applied in early clinical development for drug-drug interaction assessment.

AIMS: We aimed to incorporate a pharmacologically inactive midazolam microdose into early clinical studies for the assessment of CYP3A drug-drug interaction liability. METHODS: Three early clinical studies were conducted with substances (Compounds A, B and C) which gave positive CYP3A perpetrator signals in vitro. A 75 µg dose of midazolam was administered alone (baseline CYP3A activity) followed by administration with the highest dose groups tested for each compound on Day 1/3 and Day 14 or Day 17. Midazolam exposure (AUC0-∞ , Cmax ) during administration with the test substances was compared to baseline data via an analysis of variance on log-transformed data. Partial AUC2-4 ratios were also compared to AUC0-∞ ratios using linear regression on log-transformed data. RESULTS: Test compound Cmax values exceeded relevant thresholds for drug-drug interaction liability. Midazolam concentrations were quantifiable over the full profiles for all subjects in all studies. Point estimates of the midazolam AUC0-∞ gMean ratios ranged from 108.3 to 127.1% for Compound A, from 93.3 to 114.5% for Compound B, and from 92.0 to 96.7% for the two highest dose groups of Compound C. Cmax gMean ratios were in the same range. Thus, no relevant drug-drug interactions were evident, based on the results of midazolam microdosing. AUC2-4 ratios from these studies were comparable to the AUC0-∞ ratios. CONCLUSION: Midazolam microdosing incorporated into early clinical studies is a feasible tool for reducing dedicated drug-drug interaction studies, meaning reduced subject burden. Limited sampling could further reduce subject burden, costs and needed resources.

Low socio-economic conditions and prematurity-related morbidities explain healthcare use and costs for 2-year-old very preterm children.

AIM: To estimate healthcare use and related costs for 2-year-old very preterm (VP) children after discharge from the neonatal unit. METHODS: As part of a European project, we recruited an area-based cohort including all VP infants born in three Italian regions (Lazio, Emilia-Romagna and Marche) in 2011-2012. At 2 years corrected age, parents completed a questionnaire on their child health and healthcare use (N = 732, response rate 75.6%). Cost values were assigned based on national reimbursement tariffs. We used multivariable analyses to identify factors associated with any rehospitalisation and overall healthcare costs. RESULTS: The most frequently consulted physicians were the paediatrician (85% of children), the ophthalmologist (36%) and the neurologist/neuropsychiatrist (26%); 38% of children were hospitalised at least once after the initial discharge, for a total of 513 admissions and over one million euros cost, corresponding to 75% of total healthcare costs. Low maternal education and parental occupation index, congenital anomalies and postnatal prematurity-related morbidities significantly increased the risk of rehospitalisation and total healthcare costs. CONCLUSION: Rehospitalisation and outpatient care are frequent in VP children, confirming a substantial health and economic burden. These findings should inform the allocation of resources to preventive and rehabilitation services for these children.

Maternal Education Is Associated with Disparities in Breastfeeding at Time of Discharge but Not at Initiation of Enteral Feeding in the Neonatal Intensive Care Unit.

OBJECTIVE: To investigate the relationship between maternal education and breastfeeding in very preterm infants admitted to neonatal intensive care units. STUDY DESIGN: This prospective, population-based cohort study analyzed the data of all very preterm infants admitted to neonatal care during 1 year in 3 regions in Italy (Lazio, Emilia-Romagna, and Marche). The use of mothers' own milk was recorded at initial enteral feedings and at hospital discharge. We used multilevel logistic analysis to model the association between maternal education and breastfeeding outcomes, adjusting for maternal age and country of birth. Region was included as random effect. RESULTS: There were 1047 very preterm infants who received enteral feeding, and 975 were discharged alive. At discharge, the use of mother's own milk, exclusively or not, and feeding directly at the breast were significantly more likely for mothers with an upper secondary education or higher. We found no relationship between maternal education and type of milk at initial enteral feedings. However, the exclusive early use of the mother's own milk at initial feedings was related significantly with receiving any maternal milk and feeding directly at the breast at discharge from hospital, and the association with feeding at the breast was stronger for the least educated mothers. CONCLUSION: In this population-based cohort of very preterm infants, we found a significant and positive association between maternal education and the likelihood of receiving their mother's own milk at the time of discharge. In light of the proven benefits of maternal milk, strategies to support breastfeeding should be targeted to mothers with less education.

Priority Setting and Influential Factors on Acceptance of Pharmaceutical Recommendations in Collaborative Medication Reviews in an Ambulatory Care Setting - Analysis of a Cluster Randomized Controlled Trial (WestGem-Study).

BACKGROUND: Medication reviews are recognized services to increase quality of therapy and reduce medication risks. The selection of eligible patients with potential to receive a major benefit is based on assumptions rather than on factual data. Acceptance of interprofessional collaboration is crucial to increase the quality of medication therapy. OBJECTIVE: The research question was to identify and prioritize eligible patients for a medication review and to provide evidence-based criteria for patient selection. Acceptance of the prescribing general practitioner to implement pharmaceutical recommendations was measured and factors influencing physicians' acceptance were explored to obtain an impression on the extent of collaboration in medication review in an ambulatory care setting. METHODS: Based on data of a cluster-randomized controlled study (WestGem-study), the correlation between patient parameters and the individual performance in a medication review was calculated in a multiple logistic regression model. Physician's acceptance of the suggested intervention was assessed using feedback forms. Influential factors were analyzed. RESULTS: The number of drugs in use (p = 0.001), discrepancies between prescribed and used medicines (p = 0.014), the baseline Medication Appropriateness Index score (p<0.001) and the duration of the intervention (p = 0.006) could be identified as influential factors for a major benefit from a medication review, whereas morbidity (p>0.05) and a low kidney function (p>0.05) do not predetermine the outcome. Longitudinal patient care with repeated reviews showed higher interprofessional acceptance and superior patient benefit. A total of 54.9% of the recommendations in a medication review on drug therapy were accepted for implementation. CONCLUSIONS: The number of drugs in use and medication reconciliation could be a first rational step in patient selection for a medication review. Most elderly, multimorbid patients with polymedication experience a similar chance of receiving a benefit from a medication review. Longitudinal patient care should be preferred over confined medication reviews. The acceptance of medication reviews by physicians supports further implementation into health care systems. TRIAL REGISTRATION: ISRCTN ISRCTN41595373.

Effect evaluation of an interprofessional medication therapy management approach for multimorbid patients in primary care: a cluster-randomized controlled trial in community care (WestGem study protocol).

BACKGROUND: Pharmaceutical practice worldwide is developing towards patient care. Medication Review (MR) and Medication Therapy Management (MTM) are evolving as the most prominent services in pharmaceutical care and have a strong potential to provide a large benefit for patients and society. MTMs can only be performed in an interprofessional, collaborative setting. Several international studies have explored the effects of a MTM on the quality of therapy and costs. For Germany the data is still deficient. This study aims to provide data on the effects of an interprofessional MTM regarding quality of therapy, quality of life, costs and cost-effectiveness. METHOD/DESIGN: The study is designed as a cluster-randomized controlled trial in primary care, involving 12 outpatient clinics (clusters) and 165 patients. Primary care units are allocated to interventions using a Stepped Wedge Design. All units are initially assigned to the control group. After a 6 month observation period, general practitioners (GP) are randomly allocated to one of three groups and the interprofessional medication therapy management approach is implemented sequentially per each group with a lag of 3 months between. The primary outcome is the change in the quality of therapy measured by the MAI (Medication Appropriateness Index). Secondary outcomes include changes in the number of drug related problems, medication complexity, changes in drug-adherence, changes in health-status and function, quality of life, direct costs and the incremental cost-effectiveness ratio. The acceptance of the interprofessional Medication Therapy Management approach is assessed by qualitative methods. DISCUSSION: The patient interview and brown bag review are activities, typically provided by the pharmacist. In this trial the patient is blinded to the pharmacist. The strength of having the patient blinded to the pharmacists is to exclude skepticism of the patient toward unknown pharmacies, which might be a major confounder in a regional and community setting. A weakness is that some patient related data might reach the pharmacists in a way, which might differ from self-acquired data. TRIAL REGISTRATION: Current controlled trials ISRCTN41595373 .

Comparison of two- and three-dimensional transthoracic echocardiography to cardiac magnetic resonance imaging for assessment of paravalvular regurgitation after transcatheter aortic valve implantation.

This study evaluated 2-dimensional (2D) transthoracic echocardiography (TTE) using Valve Academic Research Consortium-2 (VARC-2) criteria and 3-dimensional (3D) TTE for assessment of aortic regurgitation (AR) after transcatheter aortic valve implantation (TAVI) in comparison with cardiac magnetic resonance (CMR) imaging. In 71 patients, 2D TTE, 3D TTE, and CMR imaging were performed to assess AR severity after TAVI. Using 2D TTE, AR severity was graded according to VARC-2 criteria and regurgitant volume (RVol) was determined. Three-dimensional color Doppler TTE allowed direct planimetry of the vena contracta area of the paravalvular regurgitation jet and calculation of the RVol as product with the velocity-time integral. RVol by CMR imaging was measured by phase-contrast velocity mapping in the ascending aorta. After TAVI, mean RVol determined by CMR imaging was 9.2 ± 9.6 ml/beat and mean regurgitant fraction was 13.3 ± 10.3%. AR was assessed as none or mild in 58 patients (82%) by CMR imaging. Correlation of 3D TTE and CMR imaging on RVol was better than correlation of 2D TTE and CMR imaging (r = 0.895 vs 0.558, p <0.001). There was good agreement between RVol by CMR imaging and by 3D TTE (mean bias = 2.4 ml/beat). Kappa on grading of AR severity was 0.357 between VARC-2 and CMR imaging versus 0.446 between 3D TTE and CMR imaging. Intraobserver variability for analysis of RVol of AR after TAVI was 73.5 ± 52.2% by 2D TTE, 16.7 ± 21.9% by 3D TTE, and 2.2 ± 2.0% by CMR imaging. In conclusion, 2D TTE considering VARC-2 criteria has limitations in the grading of AR severity after TAVI when CMR imaging is used for comparison. Three-dimensional TTE allows quantification of AR with greater accuracy than 2D TTE. Observer variability on RVol after TAVI is considerable using 2D TTE, significantly less using 3D TTE, and very low using CMR imaging.

Cardiac index assessment using bioreactance in patients undergoing cytoreductive surgery in ovarian carcinoma.

This clinical study compared the cardiac index (CI) assessed by the totally non-invasive method of bioreactance (CIBR) (NICOM™, Cheetah Medical, Vancouver, USA) to transpulmonary thermodilution (CITD) during cytoreductive surgery in ovarian carcinoma. The hypothesis was that CI could be assessed by bioreactance in an accurate and precise manner including accurate trending ability when compared to transpulmonary thermodilution. In 15 patients CIBR and CITD were assessed after induction of anesthesia, after opening of the peritoneum, hourly during the operative procedure, and 30 min after extubation. Trending ability was assessed between the described timepoints. In total 84 points of measurement were analyzed. Concordance correlation coefficient for repeated measures correlating the CIBR and CITD was 0.32. Bias was 0.26 l/min/m(2) (limits of agreement -1.39 and 1.92 l/min/m(2)). The percentage error was 50.7 %. Trending ability quantified by the mean of angles θ which are made by the ΔCI vector and the line of identity (y = x) showed a value for CIBR of θ = 23.4°. CI assessment by bioreactance showed acceptable accuracy and trending ability. However, its precision was poor. Therefore, CI measurement can not be solely based on bioreactance in patients undergoing cytoreductive surgery in ovarian carcinoma.