MPBPK-TMDD models for mAbs: alternative models,comparison, and identifiability issues

The aim of the present study was to evaluate model identifiability when minimal physiologically-based pharmacokinetic (mPBPK) models are integrated with target mediated drug disposition (TMDD) models in the tissue compartment. Three quasi-steady-state (QSS) approximations of TMDD dynamics were explored: on (a) antibody-target complex, (b) free target, and (c) free antibody concentrations in tissue. The effects of the QSS approximations were assessed via simulations, taking as reference the mPBPK-TMDD model with no simplifications. Approximation (a) did not affect model-derived concentrations, while with the inclusion of approximation (b) or (c), target concentration profiles alone, or both drug and target concentration profiles respectively deviated from the reference model profiles. A local sensitivity analysis was performed, highlighting the potential importance of sampling in the terminal pharmacokinetic phase and of collecting target concentration data. The a priori and a posteriori identifiability of the mPBPK-TMDD models were investigated under different experimental scenarios and designs. The reference model and QSS approximation (a) on antibody-target complex were both found to be a priori identifiable in all scenarios, while under the further inclusion of QSS approximation (b) target concentration data were needed for a priori identifiability to be preserved. The property could not be assessed for the model including all three QSS approximations. A posteriori identifiability issues were detected for all models, although improvement was observed when appropriate sampling and dose range were selected. In conclusion, this work provides a theoretical framework for the assessment of key properties of mathematical models before their experimental application. Attention should be paid when applying integrated mPBPK-TMDD models, as identifiability issues do exist, especially when rich study designs are not feasible.     

Serological relationship between a novel ovine pestivirus and classical swine fever virus

The genus Pestivirus comprises globally distributed members of the family Flaviviridae, which cause severe losses in livestock. The most common species of the genus are bovine viral diarrhoea virus type 1 (BVDV‐1) and type 2 (BVDV‐2), classical swine fever virus (CSFV) and border disease virus (BDV). Recently, a novel ovine pestivirus was repeatedly detected in aborted lamb foetuses on a farm located in the Brescia Province (Italy). Complete genome characterization of this isolate showed that it was highly divergent from known pestivirus species and that it was genetically closely related to CSFV. The aim of this study was to determine the serological relatedness between the identified novel pestivirus and BVDV, BDV and CSFV selected strains for which homologous serum was available, by antigenic characterization performed using cross‐neutralization assays. The serological relatedness was expressed as the coefficient of antigenic similarity (R). Both field and specific antisera raised against the ovine pestivirus neutralized the CSFV reference strain Diepholz with titres significantly higher than those specific for the BDV and BVDV strains. Furthermore, the calculated R values clearly indicated that the novel ovine pestivirus is antigenically more related to CSFV than to ruminant pestiviruses, in agreement with the results of the genomic analysis. This would have severe consequences on CSFV serology in the event of a switch to porcine hosts with implications for CSFV surveillance and porcine health management.     

Foam Replica Method in the Manufacturing of Bioactive Glass Scaffolds: Out-of-Date Technology or Still Underexploited Potential?

Since 2006, the foam replica method has been commonly recognized as a valuable technology for the production of highly porous bioactive glass scaffolds showing three-dimensional, open-cell structures closely mimicking that of natural trabecular bone. Despite this, there are important drawbacks making the usage of foam-replicated glass scaffolds a difficult achievement in clinical practice; among these, certainly the high operator-dependency of the overall manufacturing process is one of the most crucial, limiting the scalability to industrial production and, thus, the spread of foam-replicated synthetic bone substitutes for effective use in routine management of bone defect. The present review opens a window on the versatile world of the foam replica technique, focusing the dissertation on scaffold properties analyzed in relation to various processing parameters, in order to better understand which are the real issues behind the bottleneck that still puts this technology on the Olympus of the most used techniques in laboratory practice, without moving, unfortunately, to a more concrete application. Specifically, scaffold morphology, mechanical and mass transport properties will be reviewed in detail, considering the various templates proposed till now by several research groups all over the world. In the end, a comprehensive overview of in vivo studies on bioactive glass foams will be provided, in order to put an emphasis on scaffold performances in a complex three-dimensional environment.     

Predictive value of preoperative tests in discriminating bilateral adrenal hyperplasia from an aldosterone-producing adrenal adenoma

In primary hyperaldosteronism, discriminating bilateral adrenal hyperplasia (BAH) from an aldosterone-producing adenoma (APA) is important because adrenalectomy, which is usually curative in APA, is seldom effective in BAH. We analyzed the results from our most recent 7-yr series to evaluate the predictive value of preoperative noninvasive tests compared with adrenal vein sampling (AVS). Forty-eight patients with hypertensive hyperaldosteronism underwent bedside testing, computed tomography (CT) imaging, and AVS. Those in whom the results of AVS indicated APA underwent adrenalectomy. Twelve (30%) and 14 (34%) of 41 patients with APA had paradoxical falls with ambulation in plasma aldosterone concentration (PAC) and 18-hydroxycorticosterone (18-OH-B), respectively. Twenty-nine (70%) and 26 (65%) APA patients had a rise in PAC and 18-OH-B, respectively, as did all 8 BAH patients. Significant identifiers of BAH were supine PAC values less than 15 ng/dL (P: = 0.04), an increase greater than 60% (P: = 0.02) in PAC with ambulation, and supine 18-OH-B values less than 60 ng/dL (P: = 0.04). CT imaging alone was not predictive for BAH or APA. In our population, patients with a positive bedside test result (e.g. a fall in PAC and/or 18-OH-B) and a unilateral adrenal nodule on CT (10 of 41 patients) could have proceeded directly to adrenalectomy for APA. However, a positive bedside test result with a negative CT or a negative bedside test result regardless of CT findings required AVS to confirm the diagnosis and site of disease.     

Laboratory Aspirin Resistance Reversibility in Diabetic Patients: a Pilot Study Using Different Pharmaceutical Formulations

Purpose

Aspirin resistance occurs most frequently in diabetic patients and is associated with poor prognosis. The purpose of this study was to evaluate the prevalence of aspirin resistance in a cohort of diabetic patients and whether it can be reversed using more bioavailable aspirin formulations.

Methods

Platelets function of 163 diabetic patients taking acetyl salicylic acid (ASA) 100 mg daily has been evaluated with PFA100 and VerifyNow. Patients found resistant by at least one test received an infusion of 288 mg of lysine acetylsalicylate (Flectadol®) corresponding to ASA 160 mg. Platelets function was measured again after 1 and 24 h. Patients whose the resistance was reversed received 288 mg of soluble salt of lysine acetylsalicylate (Cardirene 160®) corresponding to ASA160 mg instead of aspirin and their aggregation status was re-evaluated after 1 month of therapy.

Results

Prevalence of aspirin resistance in our population was 18,4 % (30/163). In 27 out of 30 patients (90 %) aspirin resistance was reversed within 24 h from the infusion. 25 out of 27 patients (92 %) were found fully aspirin-sensitive after 1 month of oral therapy with soluble salt; two patients were found with borderline value. No adverse reactions were observed.

Conclusions

A significant number of diabetic patients are resistant to aspirin therapy. A single intravenous dose of lysine acetylsalicylate can reverse the platelet hyper-aggregability and laboratory aspirin resistance in large majority of patients. The efficacy of antiaggregation can be maintained by chronic therapy with an oral drug with a more favourable pharmacokinetic profile.     

The grandfather’s fever

Clinical Rheumatology - An 86-year-old Caucasian man had prior episodes of fever (up to 38 °C), mild abdominal pain, tachycardia, and malaise in the last 3 months, lasting...     

Linking novelty seeking and harm avoidance personality traits to cerebellar volumes

Personality traits are multidimensional traits comprising cognitive, emotional, and behavioral characteristics, and a wide array of cerebral structures mediate individual variability. Differences in personality traits covary with brain morphometry in specific brain regions, and neuroimaging studies showed structural or functional abnormalities of cerebellum in subjects with personality disorders, suggesting a cerebellar role in affective processing and an effect on personality characteristics. To test the hypothesis that cerebellar [white matter (WM) and cortex] volumes are correlated with scores obtained in the four temperamental scales of the Temperament and Character Inventory (TCI) by Cloninger, a total of 125 healthy participants aged 18–67 years of both genders (males = 52) completed the TCI and underwent magnetic resonance imaging. The scores obtained in each temperamental scale were associated with the volumes of cerebellar WM and cortex of right and left hemispheres separately by using linear regression analyses. In line with our hypothesis, novelty seeking (NS) scores were positively associated with WM and cortex cerebellar volumes. Harm avoidance (HA) scores were negatively associated with WM and cortex cerebellar volumes. The range of individual differences in NS and HA scores reflects the range of variances of cerebellar volumes. The present data indicating a cerebellar substrate for some personality traits extend the relationship between personality and brain areas to a structure up to now thought to be involved mainly in motor and cognitive functions, much less in emotional processes and even less in personality individual differences. Hum Brain Mapp 35:285–296, 2014. © 2012 Wiley Periodicals, Inc.     

Electrolyte abnormalities in cystic fibrosis: systematic review of the literature

Background

Cystic fibrosis per se can sometimes lead to hyponatremia, hypokalemia, hypochloremia or hyperbicarbonatemia. This tendency was first documented 60 years ago and has subsequently been confirmed in single case reports or small case series, most of which were retrospective. However, this issue has not been addressed analytically. We have therefore systematically reviewed and analyzed the available literature on this subject.

Methods

This was a systematic review of the literature.

Results

The reports included in this review cover 172 subacute and 90 chronic cases of electrolyte imbalances in patients with cystic fibrosis. The male:female ratio was 1.57. Electrolyte abnormalities were mostly associated with clinically inapparent fluid volume depletion, mainly affected patients aged ≤2.5 years, frequently tended to recur and often were found before the diagnosis of cystic fibrosis was established. Subacute presentation often included an history of heat exposure, vomiting, excessive sweating and pulmonary infection. History of chronic presentation, in contrast, was often inconspicuous. The tendency to hypochloremia, hypokalemia and metabolic alkalosis was similar between subacute and chronic patients, with hyponatremia being more pronounced (P?<?0.02) in subacute compared to chronic presentations. Subacute cases were treated parenterally; chronic ones were usually managed with oral salt supplementation. Retention of urea and creatinine was documented in 38 % of subacute cases.

Conclusions

The findings of our review suggest that physicians should be aware that electrolyte abnormalities can occur both as a presenting and a recurring feature of cystic fibrosis.