Towards human ex vivo organ perfusion models to elucidate drug pharmacokinetics in health and disease

Abstract

To predict the absorption, distribution, metabolism and excretion (ADME) profile of candidate drugs a variety of preclinical models can be applied. The ADME and toxicological behavior of newly developed drugs are often investigated prior to assessment in humans, which is associated with long time-lines and high costs. Therefore, good predictions of ADME profiles earlier in the drug development process are very valuable. Good prediction of intestinal absorption and renal and biliary excretion remain especially difficult, as there is an interplay of active transport and metabolism involved. To study these processes, including enterohepatic circulation, ex vivo tissue models are highly relevant and can be regarded as the bridge between in vitro and in vivo models. In this review the current in vitro, in vivo and in more detail ex vivo models for studying pharmacokinetics in health and disease are discussed. Additionally, we propose novel models, i.e., perfused whole-organs, which we envision will generate valuable pharmacokinetic information in the future due to improved translation to the in vivo situation. These machine-perfused organ models will be particularly interesting in combination with biomarkers for assessing the functionality of transporter and CYP450 proteins.     

Preventing syndemic Zika virus,HIV/STIs and unintended pregnancy: dual method use and consistent condom use among Brazilian women in marital and civil unions

Syndemic Zika virus, HIV and unintended pregnancy call for an urgent understanding of dual method (condoms with another modern non-barrier contraceptive) and consistent condom use. Multinomial and logistic regression analysis using data from the Pesquisa Nacional de Demografia e Saúde da Criança e da Mulher (PNDS), a nationally representative household survey of reproductive-aged women in Brazil, identified the socio-demographic, fertility and relationship context correlates of exclusive non-barrier contraception, dual method use and condom use consistency. Among women in marital and civil unions, half reported dual protection (30% condoms, 20% dual methods). In adjusted models, condom use was associated with older age and living in the northern region of Brazil or in urban areas, whereas dual method use (versus condom use) was associated with younger age, living in the southern region of Brazil, living in non-urban areas and relationship age homogamy. Among condom users, consistent condom use was associated with reporting Afro-religion or other religion, not wanting (more) children and using condoms only (versus dual methods). Findings highlight that integrated STI prevention and family planning services should target young married/in union women, couples not wanting (more) children and heterogamous relationships to increase dual method use and consistent condom use.     

Oral health disparities in children of immigrants: dental caries experience at enrollment and during follow-up in the New England Children's Amalgam Trial

OBJECTIVES: Previous research shows increased dental decay among immigrants, but little is known about the oral health of the growing population of children of immigrants. We compared the children of immigrants to the children of US-born caregivers in their caries experience at enrollment and their new caries increments during the 5-year New England Children's Amalgam Trial (NECAT). METHODS: NECAT recruited 283 Boston-area children aged 6 to 10 with untreated caries and offered free semiannual preventive and restorative dental care during the trial. Sociodemographic factors and caregiver immigrant status were assessed through interviews. Multivariate negative binomial models evaluated the association between caregiver immigrant status and clinically assessed carious surfaces. RESULTS: Forty percent of these Boston-area children had immigrant caregivers. At baseline, the children of immigrants had more carious surfaces (11.5 versus 9.4, adjusted for race/ethnicity, age, gender, and caregiver smoking status). Caregiver language preference explained some of this association. Immigrant status and language preference were not associated with 5-year caries increments. CONCLUSIONS: Prevalent disparities in the unmet dental needs of the immigrants' children were quickly ameliorated during participation in NECAT Dental initiatives that target neighborhoods and are sensitive to acculturation levels may help improve and maintain the oral health of immigrant families.     

Paternal influences on treatment outcome of behavioral parent training in children with attention-deficit/hyperactivity disorder

This study aims to explore the influence of paternal variables on outcome of behavioral parent training (BPT) in children with attention-deficit/hyperactivity disorder (ADHD). 83 referred, school-aged children with ADHD were randomly assigned to BPT plus ongoing routine clinical care (RCC) or RCC alone. Treatment outcome was based on parent-reported ADHD symptoms and behavioral problems. Moderator variables included paternal ADHD symptoms, depressive symptoms, and parenting self-efficacy. We conducted repeated measures analyses of variance (ANOVA) for all variables, and then analyzed the direction of interaction effects by repeated measures ANOVA in high and low scoring subgroups. Paternal ADHD symptoms and parenting self-efficacy played a moderating role in decreasing behavioral problems, but not in decreasing ADHD symptoms. Paternal depressive symptoms did not moderate either treatment outcome. BPT is most beneficial in reducing children’s behavioral problems when their fathers have high levels of ADHD symptoms or high-parenting self-efficacy.     

Procalcitonin in the recognition of complications in critically ill surgical patients

Background

Procalcitonin (PCT) is a relatively new, promising indirect parameter for infection. In the intensive care unit (ICU) it can be used as a marker for sepsis. However, in the ICU there is a need for reliable markers for clinical deterioration in the critically ill patients. This study determines the clinical value of PCT concentrations in recognizing surgical complications in a heterogeneous group of general surgical patients in the ICU.

Material and methods

We prospectively collected PCT concentration data from April 2010 to June 2012 for all general surgical patients admitted to the ICU. Both the relationships between PCT levels and events (diagnostic and therapeutic interventions) as well as between PCT levels and surgical complications (abscesses, bleeding, perforation, ischemia, and ileus) were studied.

Results

PCT concentrations were lower in patients who developed complications than those who did not develop complications on the same day, although not significant (P = 0.27). A 10% increase in PCT levels resulted in a 2% higher complication odds, but again this was not significant (odds ratio [OR], 1.020; 95% confidence interval [CI], 0.961–1.083; P = 0.51). Even a 20% or 30% increase in PCT concentrations did not result in higher complication probability (OR, 1.039; 95% CI, 0.927–1.165 and OR, 1.057; 95% CI, 0.897–1.246). Furthermore, an increase in PCT levels did not show an increase or a reduction in the number of diagnostic and therapeutic interventions.

Conclusions

An increase in PCT levels does not help to predict surgical complications in critically ill surgical patients.