The ALERRT® instrument: a quantitative measure of the effort required to compromise prescription opioid abuse-deterrent tablets

Background: US FDA guidance recommends measuring the degree of effort needed to manipulate abuse-deterrent (AD) opioids. The ALERRT^® instrument (PinneyAssociates; Bethesda, MD) uses visual analog scales to assess the labor, effort, and resources necessary to physically compromise AD product candidates in standardized settings. Objective: Use the ALERRT^® instrument for testing morphine abuse-deterrent, extended-release, injection-molded tablets (ADER-IMT) 60 and 100 mg and the comparators immediate-release (IR) morphine sulfate 30 mg and extended-release (ER) morphine sulfate 60 mg. Methods: Four technicians tested the products using 10 household tools. The ALERRT instrument quantified effort (all tools) and time (3 preselected tools) required for manipulation. Results: Morphine-ADER-IMT 60 and 100 mg were difficult to manipulate, as demonstrated by high scores (mean range, 71.0?99.0 and 77.0?99.5, respectively). IR and ER morphine sulfate were easy to manipulate (low scores; mean range, 2.0?14.8 and 2.3?17.5, respectively). Statistically significant mean differences between morphine-ADER-IMT and comparators’ ALERRT scores were observed. Manipulations of morphine-ADER-IMT 60 and 100 mg for 300 seconds failed to produce substantial powdering. Manipulations of IR morphine sulfate (mean range, 65.5?175.8 seconds) and ER morphine sulfate (49.3?163.0 seconds) produced substantial to complete powdering in 92% of tablets. Conclusions: Morphine-ADER-IMT was extremely difficult to manipulate versus non-AD formulations of morphine. The ALERRT system differentiated the degree of effort for manipulation of morphine-ADER-IMT and non-AD morphine formulations, indicating sensitivity of this instrument as part of Category 1 testing. By measuring the degree of effort required for manipulation, the ALERRT instrument provides an empirical assessment into the relative difficulty of manipulating opioid analgesics for abuse.     

A comparison between two powder compaction parameters of plasticity: The effective medium A parameter and the Heckel 1/K parameter

The purpose of the research was to introduce a procedure to derive a powder compression parameter (EM A) representing particle yield stress using an effective medium equation and to compare the EM A parameter with the Heckel compression parameter (1/K).     

Numbers and Letters: Exploring an Autistic Savant’s Unpractised Ability

This paper describes an individual with autism and high-level calendar calculation ability who could perform a set of unpractised letter/number association tasks. The savant’s performance was compared with that of two control participants, one a departmental secretary and the other a professor of mathematics. The facility with which the savant could master the rules governing the relationships between the series of items suggests that he possessed a flexibility of mental processing transcending his ability of calendar calculation. Furthermore, he could recalibrate previous knowledge to solve new hitherto unpractised tasks. When presented with novel problems, the savant, unlike the mathematician, made no initial errors at all on any of the presented tasks, thereby indicating his fast and spontaneous recognition of new rules and of new relationships between items. It is concluded that a cognitive style of ‘weak central coherence’ as adopted by autistic savants may protect single representations from being retained in the form of stable enduring wholes, and that such a segmentation strategy may allow for the transformation, reorganization and reconstruction of the relationship between single items of information.     

Application of Acoustic Bessel Beams for Handling of Hollow Porous Spheres

Acoustic manipulation of porous spherical shells, widely used as drug delivery carriers and magnetic resonance imaging contrast agents, is investigated analytically. The technique used for this purpose is based on the application of high-order Bessel beams as a single-beam acoustic manipulation device, by which particles lying on the axis of the beam can be pulled toward the beam source. The exerted acoustic radiation force is calculated using the standard partial-wave series method, and the wave propagation within the porous media is modeled using Biot's theory of poro-elasticity. Numerical simulations are performed for porous aluminum and silica shells of different thickness and porosity. Results indicate that manipulation of low-porosity shells is possible using Bessel beams with large conical angles, over a number of broadband frequency ranges, whereas manipulation of highly porous shells can occur over both narrowband and broadband frequency domains.     

屈髋屈膝按压法作用于骨盆的三维有限元分析

目的 应用有限元法研究仰卧位屈膝屈髋按压法对骨盆应力及骶髂关节应变分布特点的影响,讨论该手法扳动整个骶髂关节的可能性。方法 利用CT图像建立正常骨盆三维有限元模型。根据手法原理,将屈膝屈髋按压法分解为两个方向的力,将这两个力加载于三维有限元模型并进行计算分析,得到该加载下骨盆应力和骶髂关节应变的分布情况。结果 加载模拟手法后,骨盆的主要应力位于骶髂关节前下1/3处、坐骨大切迹及臀下线和臀前线的中1/3;骶髂关节的最大应变主要位于骶髂关节的后上缘、后下缘及上缘中部1/2。结论 屈膝屈髋按压法只能扳动骶髂关节的下1/3处,而不能扳动整个骶髂关节。     

Mast cell degranulation during abdominal surgery initiates postoperative ileus in mice

BACKGROUND & AIMS: Inflammation of the intestinal muscularis following manipulation during surgery plays a crucial role in the pathogenesis of postoperative ileus. Here, we evaluate the role of mast cell activation in the recruitment of infiltrates in a murine model. METHODS: Twenty-four hours after control laparotomy or intestinal manipulation, gastric emptying was determined. Mast cell degranulation was determined by measurement of mast cell protease-I in peritoneal fluid. Intestinal inflammation was assessed by determination of tissue myeloperoxidase activity and histochemical staining. RESULTS: Intestinal manipulation elicited a significant increase in mast cell protease-I levels in peritoneal fluid and resulted in recruitment of inflammatory infiltrates to the intestinal muscularis. This infiltrate was associated with a delay in gastric emptying 24 hours after surgery. Pretreatment with mast cell stabilizers ketotifen (1 mg/kg, p.o.) or doxantrazole (5 mg/kg, i.p.) prevented both manipulation-induced inflammation and gastroparesis. Reciprocally, in vivo exposure of an ileal loop to the mast cell secretagogue compound 48/80 (0.2 mg/mL for 1 minute) induced muscular inflammation and delayed gastric emptying. The manipulation-induced inflammation was dependent on the presence of mast cells because intestinal manipulation in mast cell-deficient Kit/Kitv mice did not elicit significant leukocyte recruitment. Reconstitution of Kit/Kitv mice with cultured bone marrow-derived mast cells from congenic wild types restored the manipulation-induced inflammation. CONCLUSIONS: Our results show that degranulation of connective tissue mast cells is a key event for the establishment of the intestinal infiltrate that mediates postoperative ileus following abdominal surgery.     

Ploidy manipulation and induction of alternate cleavage patterns through inhibition of centrosome duplication in the early zebrafish embryo

Results : A heat pulse at a later time point during the first cell cycle (22 mpf, HS2) results in a high (>80%) frequency of embryos exhibiting a precise one‐cell division stall during the second cell cycle, inducing whole genome duplication. Coupled with haploid production, HS2 generates viable gynogenetic diploids with yields up to 4 times higher than those achieved through standard Heat Shock. The cell cycle delay also causes blastomere cleavage pattern variations, supporting a role for cytokinesis in spindle orientation during the following cell cycle. 相似文献