Monetary reinforcement for self-monitoring of blood glucose among young people with type 1 diabetes: evaluating effects on psychosocial functioning.

AIMS: To explore the auxiliary psychosocial effects of a monetary reinforcement intervention targeting self-monitoring of blood glucose among young people with Type 1 diabetes. METHODS: Sixty young people with Type 1 diabetes, HbA1c concentrations between 58 and 119 mmol/mol (7.5-13.0%), and average self-monitoring of blood glucose <4 times per day were randomized to either enhanced usual care or a 24-week intervention of monetary rewards for self-monitoring of blood glucose and associated behaviours (e.g. uploading glucose meters). Data were collected from the young people and their parents at baseline, during the intervention (6, 12 and 24 weeks) and after the intervention (36 weeks). RESULTS: Linear mixed models were used to evaluate the intervention effects on psychosocial outcomes, adjusting for corresponding baseline levels and potential moderation by baseline level. The intervention reduced diabetes distress at week 6 among young people who had average and high baseline distress. It also reduced diabetes distress at weeks 12 and 24 among those with low baseline distress. The intervention also reduced young person-reported diabetes-related family conflict and diabetes-related interference among those with high baseline scores in these areas; however, the intervention worsened young person-reported diabetes interference among those with low baseline interference. Effects were medium-sized and time-limited. CONCLUSIONS: Findings indicate predominantly positive impacts of monetary reinforcement interventions on psychosocial outcomes, although effects varied by outcome and time point. Whereas early improvements in diabetes distress were observed for all who received the intervention, improvements in other areas varied according to the level of psychosocial challenge at baseline. Incorporating psychosocial interventions may bolster and maintain effects over time.

Microbial detection in seroma fluid preceding the diagnosis of breast implant-associated anaplastic large cell lymphoma: a case report and review of the literature.

The Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL) represents a topic of great concern. We report the case of a patient with late-onset seroma, who was initially diagnosed with an implant-related infection of the breast due to microbial detection in the seroma fluid, thus delaying the diagnosis of BIA-ALCL.

Perceptions about professionally and non-professionally trained hypoglycemia detection dogs.

AIMS: Patients with diabetes increasingly have questions about diabetes alert dogs. This study evaluated perceptions about dogs trained professionally or otherwise to detect glucose levels. METHODS: A link to a survey about glucose detecting dogs was announced on diabetes websites. RESULTS: 135 persons responded, with 63 answering about their child with diabetes. Most respondents obtained their dog from a professional trainer (n = 54) or trained it themselves (n = 51). Owners of self- and professionally-trained dogs were very positive about dogs' abilities to alert them to low and high glucose levels, while owners of dogs that learned entirely on their own (n = 15) reported lower frequencies of alerts and more missed hypoglycemic episodes, p<.01. Regardless of how dogs learned, perceptions about managing diabetes were improved during periods of dog ownership relative to times without, p<.001. Self-reported rates of diabetes-related hospitalizations, assistance from others for treating hypoglycemia, and accidents or near accidents while driving reduced during periods of dog ownership compared to periods without dogs, ps<.01. CONCLUSIONS: These data suggest potential effectiveness of and high satisfaction with glucose-detecting dogs. Clinicians can use these results to address pros and cons of dog ownership with patients who inquire about them.

Implications of the Institute of Medicine Report: Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease.

The Institute of Medicine (IOM) released a groundbreaking 2010 report, Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease. Key recommendations included a harmonized scientific process and a general framework for biomarker evaluation with three interrelated steps: (1) Analytical validation -- is the biomarker measurement accurate? (2) Qualification -- is the biomarker associated with the clinical endpoint of concern? (3) Utilization -- what is the specific context of the proposed use?

Measuring Biomarker Progress.

A biomarker has been defined as "a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic process, or pharmacologic responses to a therapeutic intervention." This comprehensive definition of biomarkers arose from the April 1999 US Food and Drug Administration (FDA)/National Institutes of Health consensus conference on "Biomarkers and Surrogate Endpoints: Advancing Clinical Research and Applications," and emphasized that biomarkers are medical measurements, including physiological measurements, blood tests, molecular analyses of biopsies, genetic or metabolic data, and measurements from images. Research on biomarkers-organized and propelled by this definition-has skyrocketed, with over 200,000 PubMed citations in the last five years.

First-to-patent does not predict first- or best-in-class: analysis of approved small molecule vs. biologic drugs.

The biopharmaceutical enterprise continues to analyze, refine, and identify key strategic factors predicting success of innovative therapeutic advances to address important unmet medical needs. A key comparison has focused on the relative benefits of the novel mechanism of a first-in-class drug vs. the superior properties that differentiate improved follow-on drugs (best-in-class). A corollary question to first-in-class vs. best-in-class is the impact of patent timing. Surprisingly, first-to-patent does not predict first- or best-in-class.

Calcitonin gene-related peptide: key regulator of cutaneous immunity.

Calcitonin gene-related peptide (CGRP) has been viewed as a neuropeptide and vasodilator. However, CGRP is more appropriately thought of as a pleiotropic signalling molecule. Indeed, CGRP has key regulatory functions on immune and inflammatory processes within the skin. CGRP-containing nerves are intimately associated with epidermal Langerhans cells (LCs), and CGRP has profound regulatory effects on Langerhans cell antigen-presenting capability. When LCs are exposed to CGRP in vitro, their ability to present antigen for in vivo priming of naïve mice or elicitation of delayed-type hypersensitivity is inhibited in at least some situations. Administration of CGRP intradermally inhibits acquisition of immunity to Th1-dominant haptens applied to the injected site while augmenting immunity to Th2-dominant haptens, although the cellular targets of activity in these experiments remain unclear. Although CGRP can be a pro-inflammatory agent, several studies have demonstrated that administration of CGRP can inhibit the elicitation of inflammation by inflammatory stimuli in vivo. In this regard, CGRP inhibits the release of certain chemokines by stimulated endothelial cells. This is likely to be physiologically relevant as cutaneous blood vessels are innervated by sensory nerves. Exciting new studies suggest a significant role for CGRP in the pathogenesis of psoriasis and, most strikingly, that CGRP inhibits the ability of LCs to transmit the human immunodeficiency virus 1 to T lymphocytes. A more complete understanding of the role of CGRP in the skin immune system may lead to new and novel approaches for the therapy of immune-mediated skin disorders.

Therapeutic drug monitoring as a component of personalized medicine: applications in pediatric drug development.

Therapeutic drug monitoring (TDM) is foundational to the concept of personalized medicine. TDM transformed drug therapy by affording the ability to characterize sources of variability in drug disposition and response to individualize drug dosing. Initially, TDM formed the key conceptual basis for personalized medicine, which has evolved to include pharmacogenomic and other biomarker-driven strategies for patient segmentation. Currently, TDM is an attractive option for personalized medicine and, under the right conditions, can facilitate drug development.

Incentivizing behaviour change to improve diabetes care.

Behavioural economics refers to the study of psychological and cognitive factors that relate to decision-making processes. This field is being applied increasingly to health care settings, in which patients receive tangible reinforcers or incentives for meeting objective behavioural criteria consistent with healthy lifestyles. This article reviews the background and efficacy of reinforcement interventions in general, and then as applied to behaviours related to diabetes prevention and management. Specifically, reinforcement interventions have been applied with some notable success towards promoting greater attendance at medical appointments, enhancing weight loss efforts, augmenting exercising regimes, improving medication adherence and increasing blood glucose monitoring. Suggestions for promising areas of future research are provided, keeping in mind the controversial nature of these interventions.

Pharmacokinetic evaluation of the interaction between hepatitis C virus protease inhibitor boceprevir and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors atorvastatin and pravastatin.

Boceprevir is a potent orally administered inhibitor of hepatitis C virus and a strong, reversible inhibitor of CYP3A4, the primary metabolic pathway for many 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. Thus, the aim of the present study was to investigate drug-drug interactions between atorvastatin or pravastatin and boceprevir. We conducted a single-center, open-label, fixed-sequence, one-way-crossover study with 20 healthy adult volunteers. Subjects received single-dose atorvastatin (40 mg) or pravastatin (40 mg) on day 1, followed by boceprevir (800 mg three times daily) for 7 to 10 days. Repeat single doses of atorvastatin or pravastatin were administered in the presence of steady-state boceprevir. Atorvastatin exposure increased in the presence of boceprevir, with atorvastatin area under the concentration-time curve from time zero to infinity after single dosing (AUC(inf)) increasing 2.3-fold (90% confidence interval [CI], 1.85, 2.90) and maximum observed concentration in plasma (Cmax) 2.7-fold (90% CI, 1.81, 3.90). Pravastatin exposure was slightly increased in the presence of boceprevir, with pravastatin AUC(inf) increasing 1.63-fold (90% CI, 1.03, 2.58) and C(max) 1.49-fold (90% CI, 1.03, 2.14). Boceprevir exposure was generally unchanged when the drug was coadministered with atorvastatin or pravastatin. All adverse events were mild and consistent with the known safety profile of boceprevir. The observed 130% increase in AUC of atorvastatin supports the use of the lowest possible effective dose of atorvastatin when coadministered with boceprevir, without exceeding a maximum daily dose of 40 mg. The observed 60% increase in pravastatin AUC with boceprevir coadministration supports the initiation of pravastatin treatment at the recommended dose when coadministered with boceprevir, with close clinical monitoring.

Equivalent dynamic human brain NK1-receptor occupancy following single-dose i.v. fosaprepitant vs. oral aprepitant as assessed by PET imaging.

The type 1 neurokinin receptor (NK1R) antagonist aprepitant and its i.v. prodrug fosaprepitant have been approved for prevention of acute and delayed nausea and vomiting associated with chemotherapy. This study evaluated the magnitude and duration of brain NK1R occupancy over a period of 5 days after single-dose i.v. infusion of 150-mg fosaprepitant and single-dose oral administration of 165-mg aprepitant, using serial [(18)F]MK-0999 positron emission tomography (PET) in 16 healthy subjects. Each subject underwent three scans. Brain NK1R occupancy rates after i.v. fosaprepitant at time to peak concentration (T(max); ~30 min), 24, 48, and 120 h after the dose were 100, 100, ≥97, and 41-75%, respectively. After aprepitant, NK1R occupancy rates at these time points (T(max) ~4 h) were ≥99, ≥99, ≥97, and 37-76%, respectively. Aprepitant plasma concentration profiles were comparable for the two dosage forms. The study illustrates the utility of PET imaging in determining central bioequivalence in a limited number of subjects.

UGT2B17 genetic polymorphisms dramatically affect the pharmacokinetics of MK-7246 in healthy subjects in a first-in-human study.

MK-7246, an antagonist of the chemoattractant receptor on T helper type 2 (Th2) cells, is being developed for the treatment of respiratory diseases. In a first-in-human study, we investigated whether genetic polymorphisms contributed to the marked intersubject variability in the pharmacokinetics of MK-7246 and its glucuronide metabolite M3. Results from in vitro enzyme kinetic studies suggested that UGT2B17 is probably the major enzyme responsible for MK-7246 metabolism in both the liver and the intestine. As compared with those with the UGT2B17*1/*1 wild-type genotype, UGT2B17*2/*2 carriers, who possess no UGT2B17 protein, had 25- and 82-fold greater mean dose-normalized values of area under the plasma concentration-time curve (AUC) and peak concentration of MK-7246, respectively, and a 24-fold lower M3-to-MK-7246 AUC ratio. The apparent half-life of MK-7246 was not as variable between these two genotypes. Therefore, the highly variable pharmacokinetics of MK-7246 is attributable primarily to the impact of UGT2B17 genetic polymorphisms and extensive first-pass metabolism of MK-7246.

Anacetrapib, a novel CETP inhibitor: pursuing a new approach to cardiovascular risk reduction.

Cholesteryl ester transfer protein (CETP) inhibition is a promising experimental strategy to raise high-density lipoprotein cholesterol (HDL-C) and reduce cardiovascular risk. This review focuses on the highly selective and potent CE TP inhibitor anacetrapib and discusses the available preclinical and clinical information pertaining to it. We also describe strategies to target HDL-C, discuss the mechanism underlying CETP inhibition and its effects on lipid biology, and give an overview of other CETP inhibitors that are currently in development.

[Necrotizing fasciitis caused by Acinetobacter baumannii : A case report]. / Nekrotisierende Fasziitis durch Acinetobacter baumannii : Ein Fallbericht.

A 42-year-old man developed necrotizing fasciitis on the right leg. A multidrug-resistant Acinetobacter baumannii was cultivated from the deep wound. Following therapy with imipenem and tobramycin as well as extensive debridement, the lesions improved slowly. A. baumannii is today an important cause of nosocomial infections, especially in intensive care units.

Rifampin's acute inhibitory and chronic inductive drug interactions: experimental and model-based approaches to drug-drug interaction trial design.

We studied the time course for the reversal of rifampin's effect on the pharmacokinetics of oral midazolam (a cytochrome P450 (CYP) 3A4 substrate) and digoxin (a P-glycoprotein (P-gp) substrate). Rifampin increased midazolam metabolism, greatly reducing the area under the concentration-time curve (AUC(0-∞)). The midazolam AUC(0-∞) returned to baseline with a half-life of ~8 days. Rifampin's effect on the AUC(0-3 h) of digoxin was biphasic: the AUC(0-3 h) increased with concomitant dosing of the two drugs but decreased when digoxin was administered after rifampin. Digoxin was found to be a weak substrate of organic anion-transporting polypeptide (OATP) 1B3 in transfected cells. Although the drug was transported into isolated hepatocytes, it is not likely that this transport was through OATP1B3 because the transport was not inhibited by rifampin. However, rifampin did inhibit the P-gp-mediated transport of digoxin with a half-maximal inhibitory concentration (IC(50)) below anticipated gut lumen concentrations, suggesting that rifampin inhibits digoxin efflux from the enterocyte to the intestinal lumen. Pharmacokinetic modeling suggested that the effects on digoxin are consistent with a combination of inhibitory and inductive effects on gut P-gp. These results suggest modifications to drug-drug interaction (DDI) trial designs.