Permitted daily exposure for diisopropyl ether as a residual solvent in pharmaceuticals

Solvents can be used in the manufacture of medicinal products provided their residual levels in the final product comply with the acceptable limits based on safety data. At worldwide level, these limits are set by the "Guideline Q3C (R6) on impurities: guideline for residual solvents" issued by the ICH. Diisopropyl ether (DIPE) is a widely used solvent but the possibility of using it in the pharmaceutical manufacture is uncertain because the ICH Q3C guideline includes it in the group of solvents for which "no adequate toxicological data on which to base a Permitted Daily Exposure (PDE) was found". We performed a risk assessment of DIPE based on available toxicological data, after carefully assessing their reliability using the Klimisch score approach. We found sufficiently reliable studies investigating subchronic, developmental, neurological toxicity and carcinogenicity in rats and genotoxicity in vitro. Recent studies also investigated a wide array of toxic effects of gasoline/DIPE mixtures as compared to gasoline alone, thus allowing identifying the effects of DIPE itself. These data allowed a comprehensive toxicological evaluation of DIPE. The main target organs of DIPE toxicity were liver and kidney. DIPE was not teratogen and had no genotoxic effects, either in vitro or in vivo. However, it appeared to increase the number of malignant tumors in rats. Therefore, DIPE could be considered as a non-genotoxic animal carcinogen and a PDE of 0.98 mg/day was calculated based on the lowest No Observed Effect Level (NOEL) value of 356 mg/m3 (corresponding to 49 mg/kg/day) for maternal toxicity in developmental rat toxicity study. In a worst-case scenario, using an exceedingly high daily dose of 10 g/day, allowed DIPE concentration in pharmaceutical substances would be 98 ppm, which is in the range of concentration limits for ICH Q3C guideline class 2 solvents. This result might be considered for regulatory decisions

Galectin-3 performance in histologic and cytologic assessment of thyroid nodules. A systematic review and meta-analysis

The literature on Galectin-3 (Gal-3) was systematically reviewed to achieve more robust information on its histologic reliability in identifying thyroid cancers and on the concordance between Gal-3 test in histologic and cytologic samples. A computer search of the PubMed and Scopus databases was conducted by combinations of the terms thyroid and Gal-3. Initially, 545 articles were found and, after their critical review, 52 original papers were finally included. They reported 8172 nodules with histologic evaluation of Gal-3, of which 358 with also preoperative FNAC Gal-3 assessment. At histology, Gal-3 sensitivity was 87% (95% confidence intervals [CI] from 86% to 88%), and specificity 87% (95% CI from 86% to 88%); in both cases, we found heterogeneity (I285% and 93%, respectively) and significant publication bias (p < 0.001). The pooled rate of positive Gal-3 at fine needle aspiration (FNAC) among cancers with histologically proven Gal-3 positivity was 94% (95% CI from 89% to 97%), with neither heterogeneity (I214.5%) nor bias (p = 0.086). These data show high reliability of Gal-3 for thyroid cancer at histology, while its sensitivity on FNAC samples is lower. The limits of cytologic preparations and interpretation of Gal-3 results have to be solved

The importance of reporting unexpected drug failure

Unexpected drug failure is a lack of therapeutic effect, which is not expected based on the characteristics of the drug and patient. Essentially, it may occur either for interactions (with other drugs or foods) or for biopharmaceutical issues. The risk arising from interactions is generally well characterised and physicians are well aware of it, and the importance of reporting cases of failure due to interactions is obvious. Less is known about the mechanisms and potential risk deriving from biopharmaceutical problems, and we will therefore focus on this issue. Biopharmaceutics describes the influence of the physical/chemical properties of the drug and drug product on the rate and extent of systemic drug absorption. Because after oral administration of solid pharmaceutical forms drugs must dissolve in gastrointestinal fluids before being absorbed through the intestinal epithelium, biopharmaceutical problems essentially arise from an insufficient dissolution performance. A typical situation where an insufficient dissolution may cause unexpected drug failure is when a patient is switched from one drug product to a different product. Different drug products with the same active substance may differ in manufacture and excipient composition

HDAC-inhibitor (S)-8 disrupts HDAC6-PP1 complex prompting A375 melanoma cell growth arrest and apoptosis.

Histone deacetylase inhibitors (HDACi) are agents capable of inducing growth arrest and apoptosis in different tumour cell types. Previously, we reported a series of novel HDACi obtained by hybridizing SAHA or oxamflatin with 1,4-benzodiazepines. Some of these hybrids proved effective against haematological and solid cancer cells and, above all, compound (S)-8 has emerged for its activities in various biological systems. Here, we describe the effectiveness of (S)-8 against highly metastatic human A375 melanoma cells by using normal PIG1 melanocytes as control. (S)-8 prompted: acetylation of histones H3/H4 and α-tubulin; G(0)/G(1) and G(2)/M cell cycle arrest by rising p21 and hypophos-phorylated RB levels; apoptosis involving the cleavage of PARP and caspase 9, BAD protein augmentation and cytochrome c release; decrease in cell motility, invasiveness and pro-angiogenic potential as shown by results of wound-healing assay, down-regulation of MMP-2 and VEGF-A/VEGF-R2, besides TIMP-1/TIMP-2 up-regulation; and also intracellular accumulation of melanin and neutral lipids. The pan-caspase inhibitor Z-VAD-fmk, but not the antioxidant N-acetyl-cysteine, contrasted these events. Mechanistically, (S)-8 allows the disruption of cytoplasmic HDAC6-protein phosphatase 1 (PP1) complex in A375 cells thus releasing the active PP1 that dephosphorylates AKT and blocks its downstream pro-survival signalling. This view is consistent with results obtained by: inhibiting PP1 with Calyculin A; using PPP1R2-transfected cells with impaired PP1 activity; monitoring drug-induced HDAC6-PP1 complex re-shuffling; and, abrogating HDAC6 expression with specific siRNA. Altogether, (S)-8 proved very effective against melanoma A375 cells, but not normal melanocytes, and safe to normal mice thus offering attractive clinical prospects for treating this aggressive malignancy

Toward Autonomous Guidance and Control: A Robust AI-Based Solution for Low-Thrust Orbit Transfers

The focus of our initial application scenario centers around a low-thrust orbit transfer in Low-Earth Orbit (LEO). This specific use-case has been chosen due to its inherent challenges, including the requirements for robustness and real-time computation. We propose an AI-based solution capable of autonomous and robust on-board G&C. The core of our approach leverages a Deep Neural Network (DNN) trained through Reinforcement Learning (RL) techniques. Our method aims at enhancing a traditional guidance approach by managing environmental perturbations, it processes the on-board navigation coordinates and provides the thrust to be imposed by the propulsion subsystem. Our approach demonstrates effectiveness in performing maneuvers changing semi-major axis (SMA), eccentricity (ECC), and inclination (INC), operating continuously with a control horizon of several days. Robustness is tested by using physical model uncertainties, introducing disturbances in the mission coordinates, and injecting perturbations in subsystems

Detection rate of FNA cytology in medullary thyroid carcinoma. a meta-analysis

Background: The early detection of medullary thyroid carcinoma (MTC) can improve patient prognosis, because histological stage and patient age at diagnosis are highly relevant prognostic factors. As a consequence, delay in the diagnosis and/or incomplete surgical treatment should correlate with a poorer prognosis for patients. Few papers have evaluated the specific capability of fine-needle aspiration cytology (FNAC) to detect MTC, and small series have been reported. This study conducts a meta-analysis of published data on the diagnostic performance of FNAC in MTC to provide more robust estimates. Research Design and Methods: A comprehensive computer literature search of the PubMed/MEDLINE, Embase and Scopus databases was conducted by searching for the terms 'medullary thyroid' AND 'cytology', 'FNA', 'FNAB', 'FNAC', 'fine needle' or 'fine-needle'. The search was updated until 21 March 2014, and no language restrictions were used. Results: Fifteen relevant studies and 641 MTC lesions that had undergone FNAC were included. The detection rate (DR) of FNAC in patients with MTC (diagnosed as 'MTC' or 'suspicious for MTC') on a per lesion-based analysis ranged from 12·5% to 88·2%, with a pooled estimate of 56·4% (95% CI: 52·6-60·1%). The included studies were statistically heterogeneous in their estimates of DR (I-square >50%). Egger's regression intercept for DR pooling was 0·03 (95% CI: -3·1 to 3·2, P = 0·9). The study that reported the largest MTC series had a DR of 45%. Data on immunohistochemistry for calcitonin in diagnosing MTC were inconsistent for the meta-analysis. Conclusions: The presented meta-analysis demonstrates that FNAC is able to detect approximately one-half of MTC lesions. These findings suggest that other techniques may be needed in combination with FNAC to diagnose MTC and avoid false negative results. © 2014 John Wiley & Sons Ltd

High-resolution local seismic zonation by cluster and correlation analysis

Site response analysis is essential for seismic hazard and risk assessment and for providing useful data for land-use planning. However, current regional site amplification models do not always have the resolution required for sites such as alpine valleys, in which site response is characterized by complex effects. In addition, even in local studies, site response is usually computed at a limited number of sites because it requires the recording of earthquakes through the installation of seismological stations. To spatially extend the site response to a denser grid of points inside the investigated area, we used k-means cluster and correlation analyses and Voronoi tessellation. The method was applied to the evaluation of the site response of the lower Sarca Valley on the northern shore of Lake Garda. Earthquakes were recorded at 19 sites to calculate site response in terms of amplification and duration functions of ground motion. The results show high amplification values (up to 10) at low frequencies (at about 0.7 Hz) in the center of the valley, where the sediments reach a thickness of about 420 m. Moderate amplification values and duration lengthening of several seconds in the range of 1–10 Hz are found instead at the edge of the valley on the sedimentary deposits, while a lack of amplification is observed for the sites located on the bedrock. Both the amplification and duration functions were assigned to the area covered by the single-station noise measurements to obtain a zonation of the study area, resulting in three zones to which Fourier amplification factors can be assigned for specific frequency values. The results obtained can be used directly for hazard and risk scenarios and to improve regional maps with lower resolution at the local level