Multiple doses of pegylated long‐acting growth hormone are well tolerated in healthy male volunteers and possess a potential once‐weekly treatment profile

Objectives Recombinant human growth hormone (rhGH) replacement therapy in children and adults currently requires daily subcutaneous injections for several years or lifelong. The current study examined safety, tolerability, pharmacokinetic and pharmacodynamic response parameters after single and multiple doses of a long‐acting rhGH preparation (NNC126‐0083). Design Randomized, double‐blinded, placebo‐controlled, multiple‐dose, dose‐escalating (0·02, 0·04, 0·08 and 0·16 mg protein/kg), sequential dose group trial. Subjects Forty adult Japanese healthy male volunteers (aged 20–45; body mass index: 18·0–27·0 kg/m²). Five groups (n = 8) were randomized to receive multiple doses of NNC126‐0083 (n = 6) or placebo (n = 2). Methods Primary outcome was safety, and tolerability of multiple doses of NNC126‐0083 compared with placebo. Blood samples for the assessment of pharmacokinetics (PK) and pharmacodynamics response [insulin‐like growth factor I (IGF‐I) and IGF binding protein 3 (IGFBP‐3)] were taken after multiple ascending doses. Results NNC126‐0083 was well tolerated and not associated with any local injection‐site reactions or lipoatrophy. Following administration, NNC126‐0083 levels increased rapidly and remained elevated for several days, returning to baseline before each weekly injection. Steady‐state PK was achieved after the third dosing. A more than dose‐proportional exposure was observed at the highest NNC126‐0083 dose (0·16 mg protein/kg). A strong dose‐dependent pharmacodynamic response in circulating concentrations of both IGF‐I and IGFBP‐3 compared with placebo (P < 0·0001) was observed during the administration of all doses. Conclusions Multiple administration of NNC126‐0083 in healthy male volunteers indicates that NNC126‐0083 has the potential for an efficacious, well‐tolerated, once‐weekly rhGH compound in the treatment of GH deficiency.     

Prevalence of diastolic dysfunction as a possible cause of dyspnea in the elderly

PURPOSE: Symptoms in patients with heart failure and preserved left ventricular ejection fraction may be caused by isolated diastolic dysfunction. The purpose of this study was to assess the prevalence of diastolic dysfunction as a potential cause of dyspnea in a sample of elderly subjects, as well as of isolated diastolic dysfunction as a potential cause of dyspnea in a subgroup with a preserved left ventricular ejection fraction and normal lung function. METHODS: A total of 152 subjects with dyspnea underwent echocardiography, electrocardiography, and lung function testing. Subjects with normal lung function test results (n = 60) underwent cardiac magnetic resonance imaging, chest radiography, bicycle exercise tests, and blood tests. Left ventricular diastolic function was assessed by a variety of echocardiographic/Doppler techniques. RESULTS: Of 129 subjects with dyspnea, 81 (63%) had signs of lung disease or 'obvious' cardiac disease. In the remaining 48 subjects, 32 (67%) had a potential cardiac/noncardiac cause of dyspnea. In all subjects with dyspnea, 1% to 11% had diastolic dysfunction, and in the 48 remaining subjects, 0% to 10% had isolated diastolic dysfunction, depending on the definition used. CONCLUSION: The frequency of diastolic dysfunction was low in the sample of elderly subjects with dyspnea as well as in the subgroup of persons with no signs of lung disease, left ventricular systolic dysfunction, atrial fibrillation, or valvular heart disease. Diastolic dysfunction was infrequent as a possible cause of dyspnea, and coexisting potential causes of dyspnea were often present.     

Lipoprotein(a) and Oxidized Phospholipids Promote Valve Calcification in Patients With Aortic Stenosis

Background

Lipoprotein(a) [Lp(a)], a major carrier of oxidized phospholipids (OxPL), is associated with an increased incidence of aortic stenosis (AS). However, it remains unclear whether elevated Lp(a) and OxPL drive disease progression and are therefore targets for therapeutic intervention.

Modeling Dynamic Contrast-Enhanced MRI Data with a Constrained Local AIF

Purpose

This study aims to develop a constrained local arterial input function (cL-AIF) to improve quantitative analysis of dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI) data by accounting for the contrast-agent bolus amplitude error in the voxel-specific AIF.

Procedures

Bayesian probability theory-based parameter estimation and model selection were used to compare tracer kinetic modeling employing either the measured remote-AIF (R-AIF, i.e., the traditional approach) or an inferred cL-AIF against both in silico DCE-MRI data and clinical, cervical cancer DCE-MRI data.

Results

When the data model included the cL-AIF, tracer kinetic parameters were correctly estimated from in silico data under contrast-to-noise conditions typical of clinical DCE-MRI experiments. Considering the clinical cervical cancer data, Bayesian model selection was performed for all tumor voxels of the 16 patients (35,602 voxels in total). Among those voxels, a tracer kinetic model that employed the voxel-specific cL-AIF was preferred (i.e., had a higher posterior probability) in 80 % of the voxels compared to the direct use of a single R-AIF. Maps of spatial variation in voxel-specific AIF bolus amplitude and arrival time for heterogeneous tissues, such as cervical cancer, are accessible with the cL-AIF approach.

Conclusions

The cL-AIF method, which estimates unique local-AIF amplitude and arrival time for each voxel within the tissue of interest, provides better modeling of DCE-MRI data than the use of a single, measured R-AIF. The Bayesian-based data analysis described herein affords estimates of uncertainties for each model parameter, via posterior probability density functions, and voxel-wise comparison across methods/models, via model selection in data modeling.

     

Impact of transducer frequency setting on speckle tracking measures

Speckle tracking echocardiography is an emerging technique, which is currently being included in clinical guidelines. We sought to investigate the impact of transducer frequency settings on speckle tracking derived measures. The study comprised of 22 subjects prospectively enrolled for a randomized controlled trial (LOOP-study, Clinicaltrials.gov:NCT02036450). Patients were above 70 years of age with increased risk of stroke, and had an echocardiogram performed, which included focused images of the left ventricle. Focused images were obtained with the transducer frequency set at both 1.7/3.3 and 1.5/3.0 MHz. The images were obtained immediately after each other at the exact same position for the two settings. Speckle tracking was performed in three apical projections, allowing for acquisition of layered global longitudinal strain (GLS) and strain rate measures. Concordance between the frequency settings was tested for endo-, mid-, and epicardial GLS and strain rates by coefficients of variation, bias coefficients and visually displayed by Bland–Altman plots. Bland–Altman plots did not reveal any significant over- or underestimation of any speckle tracking measure. Bias coefficients showed that none of the measurements differed significantly between the two settings (bias for GLS_endo?=???0.07?±?2.94, p?=?0.91; GLS_mid?=?0.02?±?2.70, p?=?0.98, GLS_epi?=?0.07?±?2.53, p?=?0.90). Coefficients of variation were as follows: GLS_endo?=?15.11%, GLS_mid?=?15.28%, GLS_epi?=?17.26%, systolic strain rate?=?15.66%, early diastolic strain rate?=?38.46%, late diastolic strain rate?=?11%. Changing between transducer frequency settings does not systematically derange speckle tracking measures. One can safely reduce the transducer frequency without compromising the validity of speckle tracking derived measures.     

Transient plasma cobalamin elevation in patients with pneumonia – two case reports

We report two cases of transient significantly elevated plasma cobalamin (B12) in geriatric patients acutely admitted with fever, increased C-reactive protein and X-ray verified pneumonia. Extensive diagnostic workup did not reveal kidney or liver disease, neither any signs of cancer. Furthermore, none of the patients had received therapeutic B12 supplementation prior to admission. In both cases, plasma B12 normalized at an out-patient control few months later. We were not able to identify the reason for the initial B12 elevation in any of the patients, since none of the usually recognized causes were evident. Since both patients had an infection and temporarily elevated B12, we suggest a possible inflammatory response or a vitamin B12 production by the infectious agents as the cause. Both suggestions, however, need further exploration.     

Surface‐expressed insulin receptors as well as IGF‐I receptors both contribute to the mitogenic effects of human insulin and its analogues

There is a medical need for new insulin analogues. Yet, molecular alterations to the insulin molecule can theoretically result in analogues with carcinogenic effects. Preclinical carcinogenicity risk assessment for insulin analogues rests to a large extent on mitogenicity assays in cell lines. We therefore optimized mitogenicity assay conditions for a panel of five cell lines. All cell lines expressed insulin receptors (IR), IGF‐I receptors (IGF‐IR) and hybrid receptors, and in all cell lines, insulin as well as the comparator compounds X10 and IGF‐I caused phosphorylation of the IR as well as IGF‐IR. Insulin exhibited mitogenicity EC₅₀ values in the single‐digit nanomolar to picomolar range. We observed correlations across cell types between (i) mitogenic potency of insulin and IGF‐IR/IR ratio, (ii) Akt phosphorylation and mitogenic potency and (iii) Akt phosphorylation and IR phosphorylation. Using siRNA‐mediated knockdown of IR and IGF‐IR, we observed that in HCT 116 cells the IR appeared dominant in driving the mitogenic response to insulin, whereas in MCF7 cells the IGF‐IR appeared dominant in driving the mitogenic response to insulin. Together, our results show that the IR as well as IGF‐IR may contribute to the mitogenic potency of insulin. While insulin was a more potent mitogen than IGF‐I in cells expressing more IR than IGF‐IR, the hyper‐mitogenic insulin analogue X10 was a more potent mitogen than insulin across all cell types, supporting that the hyper‐mitogenic effect of X10 involves the IR as well as the IGF‐IR. These results are relevant for preclinical safety assessment of developmental insulin analogues. Copyright © 2014 John Wiley & Sons, Ltd.