Pharmacist and student pharmacist perspectives on providing preconception care in the United States

Objectives

The primary objective was to assess pharmacist and student pharmacist current involvement and interest in providing preconception care services. Secondary objectives were to assess comfort in providing these services to various subpopulations in addition to training and resource needs.

Is there an anti-androgen withdrawal syndrome for enzalutamide?

Background

The anti-androgen withdrawal syndrome (AAWS) can be seen in one-third of patients after discontinuation of first-generation non-steroidal anti-androgen therapy. With the introduction of new agents for anti-androgen therapy as well as alternate mechanisms of action, new therapeutic options before and after docetaxel chemotherapy have arisen (Ohlmann et al. in World J Urol 30(4):495–503, 2012). The question regarding the occurrence of an enzalutamide withdrawal syndrome (EWS) has not been evaluated yet. In this study, we assess prostate-specific antigen (PSA) response after discontinuation of enzalutamide.

Methods

In total 31 patients with metastatic castration-resistant prostate cancer (mCRPC) underwent an enzalutamide withdrawal and were evaluated. Data were gathered from 6 centres in Germany. Patients with continuous oral administration of enzalutamide with rising serum PSA levels were evaluated, starting from enzalutamide withdrawal until subsequent therapy was initiated, follow-up ended or death of the patient occurred. Statistical evaluation was performed applying one-sided binomial testing using R-statistical software, version 3.0.1.

Results

Mean withdrawal follow-up was 6.5 weeks (range 1–26.1 weeks). None of the 31 patients showed a PSA decline. Mean relative PSA rise over all patients was 73.9 % (range 0.5–440.7 %) with a median of 44.9 %.

Conclusions

If existent, an AAWS is at least very rare for enzalutamide in patients with mCRPC after taxane-based chemotherapy and does not play a clinical role in this setting. This may be attributed to the different pharmacodynamics of enzalutamide. Longer duration of therapy or a longer withdrawal interval may reveal a rare EWS in the future.     

Simulations of site-specific target-mediated pharmacokinetic models for guiding the development of bispecific antibodies

Bispecific antibodies (BAbs) are novel constructs that are under development and show promise as new therapeutic modalities for cancer and autoimmune disorders. The aim of this study is to develop a semi-mechanistic modeling approach to elucidate the disposition of BAbs in plasma and possible sites of action in humans. Here we present two case studies that showcase the use of modeling to guide BAb development. In case one, a BAb is directed against a soluble and a membrane-bound ligand for treating systemic lupus erythematosus, and in case two, a BAb targets two soluble ligands as a potential treatment for ulcerative colitis and asthma. Model simulations revealed important differences between plasma and tissues, when evaluated for drug disposition and target suppression. Target concentrations at tissue sites and type (soluble vs membrane-bound), tissue-site binding, and binding affinity are all major determinants of BAb disposition and subsequently target suppression. For the presented case studies, higher doses and/or frequent dosing regimens are required to achieve 80 % target suppression in site specific tissue (the more relevant matrix) as compared to plasma. Site-specific target-mediated models may serve to guide the selection of first-in-human doses for new BAbs.     

Association of sequence variations in the gene encoding adiponectin receptor 1 (ADIPOR1) with body size and insulin levels. The Finnish Diabetes Prevention Study

Aims/hypothesis Adiponectin is a circulating peptide derived from adipose tissue. It mediates its insulin-sensitising and anti-atherogenic effects on target tissues through two known receptors, adiponectin receptors 1 and 2 (ADIPOR1; ADIPOR2), which are encoded by the genes ADIPOR1 and ADIPOR2. Our aim was to study the association of ADIPOR1 gene variations with body size and risk of type 2 diabetes in subjects with impaired glucose tolerance, who participated in the Finnish Diabetes Prevention Study (DPS).Subjects and methods We selected seven single nucleotide polymorphisms (SNPs) of the ADIPOR1 gene to perform association studies with anthropometrics and metabolic parameters at baseline, and with the risk of type 2 diabetes during the 3-year follow-up in the DPS study population. Both single SNP analysis and haplotype effects were studied.Results Three out of seven markers studied (rs10920534, rs22757538 and rs1342387) were significantly associated with various body size measurements including weight, height, waist and hip circumference, sagittal diameter and body mass index. Furthermore, three markers (rs10920534, rs12045862 and rs7539542), of which two were different from those associating with body size, were linked to fasting and 2-h insulin levels, particularly in men at baseline. The haplotype analysis with five markers revealed seven major haplotypes in the DPS study population. The haplotype effects on body size measures were in line with those of single SNP analysis. However, none of the markers were associated with the risk of type 2 diabetes.Conclusions/interpretation Our findings suggest that ADIPOR1 has a putative role in the development of body size, and that traits for central adiposity and insulin resistance may be dissociated from each other.Electronic Supplementary Material Supplementary Material is available in the online version of this article at     

Low Mediterranean Diet scores are associated with reduced kidney function and health related quality of life but not other markers of cardiovascular risk in adults with diabetes and chronic kidney disease

Background and aimsHow Mediterranean-style diets impact cardiovascular and health outcomes in patients with diabetes and chronic kidney disease (CKD) is not well known. Our aim was to investigate the association between diet quality, using Mediterranean Diet Scores (MDS) and health outcomes.Methods and resultsThis is a post-hoc analysis of an RCT and longitudinal study investigating patients with diabetes and CKD. MDS was calculated annually. Scores were analyzed for correlation with lipids, HbA_1c, serum potassium, health-related quality of life (HRQOL) and depression. 178 diet records from 50 patients who attended two or more visits were included. Mean MDS was moderate (4.1 ± 1.6) and stable over time. Stage 1–2 vs 3–5 CKD had lower raw MDS (3.8 ± 1.5 vs 4.6 ± 1.5, p < 0.001). Having hyperkalemia was associated with a lower raw MDS scores (3.6 ± 1.6 vs 4.2 ± 1.5, p = 0.03) but not energy adjusted MDS. MDS was not associated with HbA_1c or lipids. High vs low MDS was associated with improved HRQOL (mental health 84.4 ± 14.3 vs 80.3 ± 17.1, p < 0.05; general health 62.6 ± 21.0 vs 56.3 ± 19.8, p < 0.001) and fewer depressive symptoms (9.1 ± 7.4 vs 11.7 ± 10.6, p = 0.01).ConclusionsLow MDS was associated with reduced kidney function and health related quality of life, but not other markers of cardiovascular risk. Further studies are needed to understand the nature and direction of the association between diet quality and disease outcomes in this population.     

Expression patterns and functional evaluation of the UNC5B receptor during the early phase of peripheral nerve regeneration using the mouse median nerve model

Introduction: In this study, we evaluated the role of the Netrin‐1 receptor UNC5b (Uncoordinated), a neuronal guidance molecule, during peripheral nerve regeneration using the mouse median nerve model. Materials and methods: Using Western blot analysis, we examined the expression changes of UNC5b after transection and microsurgical repair of the mouse median nerve distal to the transection site. We evaluated the histomorphometrical changes and functional recovery of the grasping force after median nerve transection and repair in wild‐type (WT) mice and UNC5b^+/? heterozygous mice. Results: In Western blot analysis, we could show a high increase of UNC5b in the nerve segment distal to the injury site at day 14. Histomorphometrical analysis did not show any significant differences between WT animals and heterozygous animals. Using the functional grasping test, we could demonstrate that peripheral nerve regeneration is significantly diminished in heterozygous UNC5b^+/? mice. Conclusion: By using the mouse median nerve model in transgenic animals, we demonstrate that the Netrin‐1 receptor UNC5b plays an important role during peripheral nerve regeneration. © 2012 Wiley Periodicals, Inc. Microsurgery, 2013.     

Development of translational pharmacokinetic-pharmacodynamic models

Contemporary models in the field of pharmacokinetic-pharmacodynamic (PK-PD) modeling often incorporate the fundamental principles of capacity limitation and operation of turnover processes to describe the time course of pharmacological effects in mechanistic terms. This permits the identification of drug- and system-specific factors that govern drug responses. There is considerable interest in utilizing mechanism-based PK-PD models in translational pharmacology, whereby in silico, in vitro, and preclinical data may be effectively coupled with relevant models to streamline the discovery and development of new therapeutic agents. These translational PK-PD models form the subject of this review.