Efficacy of dapagliflozin as an adjunct therapy in patients with inadequately controlled type 1 diabetes mellitus

Introduction: There is a clear unmet clinical need in people with Type 1 diabetes (T1DM) considering present day insulin therapy. New insulin analogues and novel technologies allowing more tailored insulin administration have improved the quality of life of people with T1DM, but issues like hypoglycemia, weight gain and variability in glucose profiles remain problematic.

Areas covered: In this review, the clinical efficacy, safety and tolerability of dapagliflozin, a sodium-glucose cotransporter type 2 inhibitor, in type 1 diabetes (T1DM) is described based on a review of phase 2 and 3 studies to date.

Expert opinion: Dapagliflozin has shown promising results as an adjunct therapy in T1DM, resulting in better glucose control, weight loss and lower blood pressure. No increase in hypoglycemia risk, in particular severe hypoglycemia, was observed, but, in comparison with reports in Type 2 diabetes (T2DM), genital infections were more prevalent. Dapagliflozin use was accompanied with decreases in insulin doses, but, to date, only a low risk of diabetic ketoacidosis (DKA) was reported. However, caution is needed when interpreting this data, arising from well controlled clinical trials, with intensive education programs around ketone measurements and DKA prevention. Further studies will need to establish how high the DKA risk is and how to mitigate this in a real-world setting.     

Medication management in Minnesota schools: The need for school nurse–pharmacist partnerships

Background

Pharmacist participation in school medication management (MM) is minimal. School nurses are responsible for increasingly complex medication administration and management in schools.

Nephrotoxicity and Kidney Transport Assessment on 3D Perfused Proximal Tubules

Proximal tubules in the kidney play a crucial role in reabsorbing and eliminating substrates from the body into the urine, leading to high local concentrations of xenobiotics. This makes the proximal tubule a major target for drug toxicity that needs to be evaluated during the drug development process. Here, we describe an advanced in vitro model consisting of fully polarized renal proximal tubular epithelial cells cultured in a microfluidic system. Up to 40 leak-tight tubules were cultured on this platform that provides access to the basolateral as well as the apical side of the epithelial cells. Exposure to the nephrotoxicant cisplatin caused a dose-dependent disruption of the epithelial barrier, a decrease in viability, an increase in effluent LDH activity, and changes in expression of tight-junction marker zona-occludence 1, actin, and DNA-damage marker H2A.X, as detected by immunostaining. Activity and inhibition of the efflux pumps P-glycoprotein (P-gp) and multidrug resistance protein (MRP) were demonstrated using fluorescence-based transporter assays. In addition, the transepithelial transport function from the basolateral to the apical side of the proximal tubule was studied. The apparent permeability of the fluorescent P-gp substrate rhodamine 123 was decreased by 35% by co-incubation with cyclosporin A. Furthermore, the activity of the glucose transporter SGLT2 was demonstrated using the fluorescent glucose analog 6-NBDG which was sensitive to inhibition by phlorizin. Our results demonstrate that we developed a functional 3D perfused proximal tubule model with advanced renal epithelial characteristics that can be used for drug screening studies.     

Switching cell penetrating and CXCR4-binding activities of nanoscale-organized arginine-rich peptides

Arginine-rich protein motifs have been described as potent cell-penetrating peptides (CPPs) but also as rather specific ligands of the cell surface chemokine receptor CXCR4, involved in the infection by the human immunodeficiency virus (HIV). Polyarginines are commonly used to functionalize nanoscale vehicles for gene therapy and drug delivery, aimed to enhance cell penetrability of the therapeutic cargo. However, under which conditions these peptides do act as either unspecific or specific ligands is unknown. We have here explored the cell penetrability of differently charged polyarginines in two alternative presentations, namely as unassembled fusion proteins or assembled in multimeric protein nanoparticles. By this, we have observed that arginine-rich peptides switch between receptor-mediated and receptor-independent mechanisms of cell penetration. The relative weight of these activities is determined by the electrostatic charge of the construct and the oligomerization status of the nanoscale material, both regulatable by conventional protein engineering approaches.     

The intraocular staining potential of anthocyanins and their retinal biocompatibility: a preclinical study

Purpose: To perform preclinical studies to determine the efficacy and safety of anthocyanins as stains for the internal limiting membrane (ILM) of the eye.

Materials and methods: Cyanidin (Cya), delphinidin (Del), luteolinidin (Lut), peonidin (Peo) and pelargonidin (Pel) were evaluated. These natural dyes were used to stain the lens capsule and ILM of pig eyes. The effects of these dyes on retinal cell viability was determined using a water-soluble tetrazolium salt assay, and oxidative stress was measured in vitro. Histopathology, in situ TUNEL labelling, transmission electronic microscopy (TEM), and electroretinography (ERG) were performed on rats following the intravitreal and subretinal injection of the neuroprotective dyes.

Results: All anthocyanins stained the lens capsule and ILM of the pigs at a concentration of 1?mg/ml. Del, Lut and Peo were non-toxic and produced survival rates in the ARPE19 and RGC5 cells that were similar to those in control cells. We treated eyes with H₂O₂ and three dyes (Del, Lut, and Peo) to explore the possible neuroprotective effects and observed significantly higher survival rates in the ARPE19 cells treated with Del, Lut or Peo and the RGC5 cells treated with Lut or Peo than those in the control cells. Three dyes were intravitreally and subretinally injected into rats in vivo, and the histology showed mildly disorganized retinal cell layers. TUNEL staining and TEM examinations did not reveal additional toxic effects. Rat ERGs were not altered after intravitreal injections.

Conclusions: This preclinical study, Del, Lut, and Peo show potential as staining agents and warrant further investigation as vital dyes.     

Maternal Multivitamin Intake,Plasma Folate and Vitamin B12 Levels and Autism Spectrum Disorder Risk in Offspring

Background

To examine the prospective association between multivitamin supplementation during pregnancy and biomarker measures of maternal plasma folate and vitamin B₁₂ levels at birth and child's Autism Spectrum Disorder (ASD) risk.

Methods

This report included 1257 mother–child pairs, who were recruited at birth and prospectively followed through childhood at the Boston Medical Center. ASD was defined from diagnostic codes in electronic medical records. Maternal multivitamin supplementation was assessed via questionnaire interview; maternal plasma folate and B₁₂ were measured from samples taken 2–3 days after birth.

Results

Moderate (3–5 times/week) self‐reported supplementation during pregnancy was associated with decreased risk of ASD, consistent with previous findings. Using this as the reference group, low (≤2 times/week) and high (>5 times/week) supplementation was associated with increased risk of ASD. Very high levels of maternal plasma folate at birth (≥60.3 nmol/L) had 2.5 times increased risk of ASD [95% confidence interval (CI) 1.3, 4.6] compared to folate levels in the middle 80th percentile, after adjusting for covariates including MTHFR genotype. Similarly, very high B₁₂ (≥536.8 pmol/L) showed 2.5 times increased risk (95% CI 1.4, 4.5).

Conclusion

There was a ‘U shaped’ relationship between maternal multivitamin supplementation frequency and ASD risk. Extremely high maternal plasma folate and B₁₂ levels at birth were associated with ASD risk. This hypothesis‐generating study does not question the importance of consuming adequate folic acid and vitamin B₁₂ during pregnancy; rather, raises new questions about the impact of extremely elevated levels of plasma folate and B₁₂ exposure in‐utero on early brain development.     

Agreeableness and pregnancy: Relations with coping and psychiatric symptoms,a longitudinal study on Spanish pregnant women

ABSTRACT

Agreeableness is associated with good mental health during pregnancy. Although different studies have indicated that agreeableness is related to adaptive coping, this relation has scarcely been studied in pregnant women. The aim of this study was to analyze the possible differences between high and low agreeableness in relation to coping strategies and psychiatric symptoms in pregnant women. We conducted a longitudinal prospective study between October 2009 and January 2013. Pregnant women (n = 285) were assessed in the first trimester of pregnancy, and 122 of them were assessed during the third. Data were collected using the Coping Strategies Questionnaire, the Symptom Check List 90-R, and the agreeableness subscale of the NEO-FFI. Using the SPSS 21 statistics package, binary logistic regression, two-way mixed analysis of variance, and multiple regression analyses and a Sobel test were conducted. Higher levels of agreeableness were associated with positive reappraisal and problem-solving, and lower levels of agreeableness were associated with overt emotional expression and negative self-focused coping. Women with low agreeableness had poorer mental health, especially in the first trimester. These findings should be taken into account to improve women’s experiences during pregnancy. Nevertheless, given the scarcity of data, additional studies are needed.