DPP-4 Inhibitor Dose Selection According to Manufacturer Specifications: A Contemporary Experience From UK General Practice.

Recently, 2 dipeptidyl peptidase-4 (DPP-4) inhibitors, sitagliptin and saxagliptin, adjusted dosing specification from creatinine clearance to glomerular filtration rate, more typically reported in routine laboratory tests. This cross-sectional study examines all DPP-4 inhibitor initiations that require dose adjustment and the dose selection using data from UK general practice. Results indicate that 34% of patients taking a nonlinagliptin DPP-4 inhibitor were given a higher dose and 11% a lower dose than specified in the Summary of Product Characteristics. This reinforces the deviation from Summary of Product Characteristics prescription of DPP-4 inhibitors identified in earlier studies despite improvement in compatibility with routine reporting.

Temporal variation of renal function in people with type 2 diabetes mellitus: A retrospective UK clinical practice research datalink cohort study.

AIM: To characterize the longitudinal variability of estimated glomerular filtration rate (eGFR) in people with type 2 diabetes mellitus (T2DM), including variation between categories and individuals. METHODS: People with T2DM and sufficient recorded serum creatinine measurements were identified from the Clinical Practice Research Datalink (T2DM diagnosis from 1 January 2009 to 1 January 2011 with 5 years follow-up); eGFR was calculated using the CKD-EPI equation. RESULTS: In total, 7766 individuals were included; 32.8%, 50.2%, 12.4%, 4.0% and 0.6% were in glomerular filtration rate (GFR) categories G1, G2, G3a, G3b and G4, respectively. Overall, eGFR decreased by 0.44 mL/min/1.73 m2 per year; eGFR increased by 0.80 mL/min/1.73 m2 between index and year 1, then decreased by 0.75 mL/min/1.73 m2 annually up to year 5. Category G1 showed a steady decline in eGFR over time; G2, G3a and G3b showed an increase between index and year 1, followed by a decline. Category G4 showed a mean eGFR increase of 1.85 mL/min/1.73 m2 annually. People in categories G3-G4 moved across a greater number of GFR categories than those in G1 and G2. Individual patients' eGFR showed a wide range of values (change from baseline at year 5 varied from -80 to +59 mL/min/1.73 m2 ). CONCLUSION: Overall, eGFR declined over time, although there was considerable variation between GFR categories and individuals. This highlights the difficulty in prescribing many glucose-lowering therapies, which require dose adjustment for renal function. The study also emphasizes the importance of regular monitoring of renal impairment in people with T2DM.

Prescription of DPP-4 Inhibitors to Patients With Adult Type 2 Diabetes Mellitus and Creatinine Clearance >50 mL/min: The UK Primary Care Experience.

The aim of the study was to examine the extent to which patients with type 2 diabetes mellitus (T2DM) initiating a dipeptidyl peptidase 4 (DPP-4) inhibitor, who had no recorded objective evidence to justify dose adjustment, were initiated on the manufacturer-specified dose. Adopting a cross-sectional study design and using data from the UK General Practice, this study showed that at least 10% of patients with T2DM and a creatinine clearance level >50 mL/min initiating treatment with a DPP-4 inhibitor were prescribed a dose lower than specified in the Summary of Product Characteristics. This study provides further insights regarding DPP-4 inhibitor dose selection with respect to manufacturer specification in relation to renal function.

Prescription of DPP-4 Inhibitors to Type 2 Diabetes Mellitus Patients With Renal Impairment: A UK Primary Care Experience.

Members of the dipeptidyl peptidase-4 inhibitor drug class are indicated for glycemic control in patients with type 2 diabetes mellitus and all, except linagliptin, require dose adjustment in renal impairment. A cross-sectional analysis of a cohort of type 2 diabetes mellitus patients treated with dipeptidyl peptidase-4 inhibitors identified in the Clinical Practice Research Datalink was conducted to explore compliance with the renal adjustment requirements of the Summaries of Product Characteristics. Approximately one third of type 2 diabetes mellitus patients with creatinine clearance <50 mL/min who were at risk of inappropriate prescribing, were initiated on a DPP-4 inhibitor at a higher dose than the specified in their respective Summary of Product Characteristics.

Estimating the modulatory effects of nanoparticles on neuronal circuits using computational upscaling.

BACKGROUND: Beside the promising application potential of nanotechnologies in engineering, the use of nanomaterials in medicine is growing. New therapies employing innovative nanocarrier systems to increase specificity and efficacy of drug delivery schemes are already in clinical trials. However the influence of the nanoparticles themselves is still unknown in medical applications, especially for complex interactions in neural systems. The aim of this study was to investigate in vitro effects of coated silver nanoparticles (cAgNP) on the excitability of single neuronal cells and to integrate those findings into an in silico model to predict possible effects on neuronal circuits. METHODS: We first performed patch clamp measurements to investigate the effects of nanosized silver particles, surrounded by an organic coating, on excitability of single cells. We then determined which parameters were altered by exposure to those nanoparticles using the Hodgkin-Huxley model of the sodium current. As a third step, we integrated those findings into a well-defined neuronal circuit of thalamocortical interactions to predict possible changes in network signaling due to the applied cAgNP, in silico. RESULTS: We observed rapid suppression of sodium currents after exposure to cAgNP in our in vitro recordings. In numerical simulations of sodium currents we identified the parameters likely affected by cAgNP. We then examined the effects of such changes on the activity of networks. In silico network modeling indicated effects of local cAgNP application on firing patterns in all neurons in the circuit. CONCLUSION: Our sodium current simulation shows that suppression of sodium currents by cAgNP results primarily by a reduction in the amplitude of the current. The network simulation shows that locally cAgNP-induced changes result in changes in network activity in the entire network, indicating that local application of cAgNP may influence the activity throughout the network.

Modeling the influences of nanoparticles on neural field oscillations in thalamocortical networks.

The purpose of this study is twofold. First, we present a simplified multiscale modeling approach integrating activity on the scale of ionic channels into the spatiotemporal scale of neural field potentials: Resting upon a Hodgkin-Huxley based single cell model we introduced a neuronal feedback circuit based on the Llinás-model of thalamocortical activity and binding, where all cell specific intrinsic properties were adopted from patch-clamp measurements. In this paper, we expand this existing model by integrating the output to the spatiotemporal scale of field potentials. Those are supposed to originate from the parallel activity of a variety of synchronized thalamocortical columns at the quasi-microscopic level, where the involved neurons are gathered together in units. Second and more important, we study the possible effects of nanoparticles (NPs) that are supposed to interact with thalamic cells of our network model. In two preliminary studies we demonstrated in vitro and in vivo effects of NPs on the ionic channels of single neurons and thereafter on neuronal feedback circuits. By means of our new model we assumed now NPs induced changes on the ionic currents of the involved thalamic neurons. Here we found extensive diversified pattern formations of neural field potentials when comparing to the modeled activity without neuromodulating NPs addition. This model provides predictions about the influences of NPs on spatiotemporal neural field oscillations in thalamocortical networks. These predictions can be validated by high spatiotemporal resolution electrophysiological measurements like voltage sensitive dyes and multiarray recordings.

Efficacy and augmentation during 6 months of double-blind pramipexole for restless legs syndrome.

BACKGROUND: Pramipexole is an effective treatment for restless legs syndrome (RLS), but no controlled studies have lasted >12 weeks. METHODS: RLS patients (N=331) with pretreatment serum ferritin >30 ng/mL were randomly assigned to take double-blind optimized pramipexole (0.125-0.75 mg/d) or placebo for 26 weeks. The primary efficacy endpoint was change in International RLS Study Group Rating Scale (IRLS) score. Other endpoints assessed global change, symptoms, and QoL. Patients maintained symptom diaries. Cases meeting predefined criteria for suspected augmentation were reviewed by a blinded expert panel, which used a predefined algorithm. RESULTS: Among 321 patients providing post-baseline data, of whom 234 completed 26 weeks, pramipexole was more effective than placebo by multiple endpoints, including an adjusted mean IRLS score change of -13.7 vs. -11.1 (p=0.0077) and an IRLS responder rate (≥50% score reduction) of 58.6% vs. 42.8% (p=0.0044). Efficacy showed considerable country-to-country variability. Six-month incidence of confirmed augmentation was 9.2% for pramipexole and 6.0% for placebo. The rate increased with treatment duration for pramipexole but not placebo. Treatment-related adverse events (AEs) were more likely for pramipexole than for placebo, but discontinuation due to AEs was less likely. CONCLUSIONS: During a 6-month period, pramipexole was effective, safe, and generally well tolerated. Because risk of augmentation may have increased over 6 months, it should be studied in longer trials. Beginning or mild augmentation is difficult to distinguish from natural RLS fluctuation, at least in a non-iron-deficient population.

Evaluation of painful sensory symptoms in restless legs syndrome: experience from two clinical trials.

BACKGROUND: Although "uncomfortable and unpleasant" limb sensations are a core symptom of restless legs syndrome (RLS), change in sensory symptomatology is usually not evaluated as a treatment outcome. METHODS: In two double-blind trials, patients with idiopathic RLS (n=357 in trial 615 and 398 in trial 604) were randomized to placebo or pramipexole (optimized at 0.125, 0.25, 0.50, or 0.75 mg/day). For entry, trial 604 also required at least moderate mood disturbance. In both trials, 12-week change in RLS-related limb pain was assessed using a 100-mm visual analogue scale (VAS). RESULTS: At baseline, approximately 75% of patients had limb-pain scores >30. Treatment with pramipexole yielded significant score reduction as early as day 5. At week 12, median score reduction for pramipexole relative to placebo was -33.5 vs. -11.0 (p<0.0001) in trial 615 and -31.0 vs. -11.0 (p<0.0001) in trial 604. CONCLUSIONS: Painful sensations may be more frequent in RLS than has previously been appreciated, and their amelioration may be a facet of pramipexole's benefit even in patients with concurrent mood disturbance. Limb pain assessment, e.g., by a VAS, is a useful measure of change in RLS symptom severity.

Modeling the effects of nanoparticles on neuronal cells: from ionic channels to network dynamics.

Engineered nanoparticles (NPs) offer great application potential in various fields, for example the chemical industry, energy management or medical sciences. Nanoparticles are increasingly being incorporated into daily products. But what happens, if living organisms are exposed to those NPs? Their ability to move seemingly barrier-free in organic tissue could be both beneficial and harmful. Even though research concerning nanotoxicity has already begun, there are still many open questions to be addressed. In this report, we propose a computational model applying the steady-state Hodgkin-Huxley-equations and the Differential Evolution Algorithm for fitting the model to the data of patch-clamp measurements carried out by our group: Coated silvernanoparticles (Ag-Nano) in different concentrations were applied to single chromaffin cells while measuring the ionic currents in the whole-cell configuration. Compared to controls, significant differences in sodium-currents were observed after the application of NPs. Using the computational model, we could evaluate the parameters which model the change in behavior of neuronal cells due to the addition of Ag-Nano. This can ultimately give insight to underlying mechanisms. An integration to model the dynamic behavior of neuronal networks exposed to NP is easily conceivable using this technique.

Assessment of aversive stimuli dependent attentional binding by the N170 VEP component.

For social species nonverbal communication by assessment of emotion expression is crucial for building up and maintaining social structures. In humans, body language not only includes gestures but also a variety of facial expressions. Negative associated facial expressions, e.g. disgust, fear, anger call for a higher attentional binding due their evolutionary background, denoting directly personal dangers for the receptive individual. In a number of psychiatric disorders such as schizophrenia or autism spectrum diseases, the assessment of emotions in faces is disturbed, leading to even more pronounced social cuts. In this article we present a new methodology for monitoring the attentional binding to emotion-tinged stimuli in a face recognition task. We were able to demonstrate a significant difference in habituation behavior to neutral and negative associated faces respectively. In future, this methodology might provide a fast and reliable scheme for the detection of psychiatric disorders comprising dysfunction of limbic structures.

Neurofeedback by neural correlates of auditory selective attention as possible application for tinnitus therapies.

More and more people are suffering from tinnitus. There are many treatments for tinnitus that have been claimed based on different causes. Unfortunately, until now none of the existing treatments has been found to be effective in general. Here, we would like to suggest a treatment to tinnitus based on neurofeedback using neural correlates of auditory selective evoked potentials (ASEPs). We have shown that the wavelet phase synchronization of auditory late responses (ALR) single sweeps allows for a direct online monitoring of phase locked auditory attention. The results show that after a simple training, subjects learned to control their attention to the auditory modality. To improve the ability in the attention control system is an objective of many tinnitus treatments, so that the perception of the patients towards the tinnitus noise can be reduced to a minimum. It is concluded that our proposed neurofeedback system by wavelet phase synchronization measure might be used in a clinical treatment of tinnitus patients and it is possible to extent to other therapeutic based control systems.

The placebo effect in the pharmacologic treatment of patients with lower urinary tract symptoms.

OBJECTIVES: We reviewed placebo responses in randomised controlled trials (RCTs) for pharmacologic treatment of lower urinary tract symptoms (LUTS), including urinary incontinence (UI), overactive bladder, and benign prostatic hyperplasia. Review papers on placebo effects in non-urologic disorders were assessed to compare the magnitude of placebo responses in drugs for LUTS with those reported for other diseases. METHODS: Data were retrieved from registration trials for LUTS drugs on the Web sites of the Food and Drugs Administration and the European Medicines Agency. Reviews were retrieved from Medline using the MeSH term "placebo effect" (English language; published between 1990 and 2005). RESULTS: Placebo treatment of LUTS yields reductions in incontinence episodes (IEs) ranging from 32% to 65%, whereas prostate or UI symptom scores are reduced by 9-34%. Genuine drugs decrease IEs by 45-77% and symptom scores by 22-45%. Placebo responses are much lower when objective changes in voided volume or peak flow rate are assessed. CONCLUSIONS: The placebo effect in LUTS has a strong behavioural component as patients become aware of their voiding habits and potential risk factors. Symptom severity, treatment naivety, study duration, and interaction with health care providers may also influence it. Proper patient selection, study duration, and objective and subjective outcome measures may better separate genuine treatment effects from artefacts. Observational studies with patients representative for real-life situations and covering a sufficient period of time could allow for better understanding of RCT results and their applicability in clinical practice.