Statistical Experimental Design and its Application to Pharmaceutical Development Problems

Pharmaceutical scientists are often confronted with the problem of developing formulations and processes for difficult products and must do so in spite of competing objectives. Pressures, placed on the scientist to balance variables and meet these objectives, can be compounded when limited funds, time and resources require rapid and accurate development activities. Statistical experimental designs provide an economical way to efficiently gain the most information while expending the least amount of experimental effort

Some commonly used techniques called Response Surface Designs are presented. These include the Central Composite, Extreme Vertices, Simplex and Evolutionary Operations designs. Procedures for planning experiments and for analyzing and interpreting data are also discussed. Guidance is provided on the implementation of experimental results and the practical use of these techniques for routine experiments     

Inhibition of the microsomal triglyceride transfer protein blocks the first step of apolipoprotein B lipoprotein assembly but not the addition of bulk core lipids in the second step

The microsomal triglyceride transfer protein (MTP) is required for assembly and secretion of the lipoproteins containing apolipoprotein B (apoB): very low density lipoproteins and chylomicrons. Evidence indicates that the subclasses of these lipoproteins that contain apoB-48 are assembled in a distinct two-step process; first a relatively lipid-poor primordial lipoprotein precursor is produced, and then bulk neutral lipids are added to form the core of these spherical particles. To determine if either step is mediated by MTP, a series of clonal cell lines stably expressing apoB-53 and MTP was established in non-lipoprotein-producing HeLa cells. MTP activity in these cells was approximately 30%, and apoB secretion was 7-33% of that in HepG2 cells on a molar basis. Despite having robust levels of triglyceride and phospholipid synthesis, these cell lines, as exemplified by HLMB53-59, secreted >90% of the apoB-53 on relatively lipid-poor particles in the density range of 1.063-1.21 g/ml. These results suggested that coexpression of MTP and apoB only reconstituted the first but not the second step in lipoprotein assembly. To extend this observation, additional studies were carried out in McArdle RH-7777 rat hepatoma cells, in which the second step of apoB-48 lipoprotein assembly is well defined. Treatment of these cells with the MTP photoaffinity inhibitor BMS-192951 before pulse labeling with [35S]methionine/cysteine led to an 85% block of both apoB-48 and apoB-100 but not apoAI secretion, demonstrating inhibition of the first step of lipoprotein assembly. After a 30-min [35S]methioneine/cysteine pulse labeling and 120 min of chase, all of the nascent apoB-48 was observed to have a density of high density lipoproteins (1.063-1.21 g/ml), indicating that only the first step of lipoprotein assembly had occurred. The addition of oleic acid to the cell culture media activated the second step as evidenced by the conversion of the apoB-48 high density lipoproteins to very low density lipoproteins (d < 1.006 g/ml) during an extended chase period. Inactivation of MTP after completion of the first step, but before stimulation of the second step by the addition of oleic acid, did not block this conversion. Thus, inhibition of MTP did not hinder the addition of bulk core lipid to the primordial lipoprotein precursor particles, indicating that MTP is not required for the second step of apoB-48 lipoprotein assembly.     

cis-Diaminedichloroplatinum(II) complexes reversibly bound to water-soluble polyaspartamide carriers for chemotherapeutic applications. II: Platinum coordination to ethylenediamine ligands attached to poly(ethylene oxide)-grafted carrier polymers

In continuation of previous investigations aiming at the development of macromolecular metal complexes for biomedical use, this communication describes poly(alkylene oxide)-grafted polymeric platinum complexes. The platinum-containing macromolecules are obtained from presynthesized polyaspartamide carriers bearing poly(ethylene/propylene oxide) side chains and hydroxyethyl side groups as hydrosolubilizing units in addition to ethylenediamine side group terminals for metal coordination. Platination is brought about by treatment of the carriers with tetrachloroplatinate(II) ion in aqueous solution at 25–60°C. pH 4–6. The polymeric products, purified by dialysis in aqueous solution, are isolated by freeze-drying in yields of 60–80%. Platinum contents are in the range of 4–15%. The metal is bound to the carrier through chelation with the ethylenediamine ligands, forming square-planarcis-dichloroethylenediamine-platinum(II) complex species as side-chain terminals. Initially, the product polymers dissolve smoothly in water. Although on room-temperature storage in the solid state they gradually turn insoluble as a consequence of intermolecular solid-state interaction, solubility is retained on low-temperature storage and in frozen aqueous solutions.Presented in part at the Fifth International Symposium on Macromolecule-Metal Complexes. September 29–October 3, 1993. Bremen, Germany. For Part I of this Series, see Ref. 1.     

Computerized work management one city, one system

Picture this if you can. There are fifteen work crews and thirteen of these are sitting at McDonald's drinking a cup of coffee. Sound familiar? This situation often arises not from not having enough work to do, but in deciding what work is most important and should be performed first. This brings us to the topic of this paper — The City of Arlington Work Management System. Arlington has a population of 220,000, and is situated midway between Dallas and Fort Worth.

The proposed paper explains the design and development of the on-line System, including problems encountered during the design phase of the System and future developments. It will also discuss how the System allocates crews, and schedules and tracks Work Orders for different areas of the City.

The paper will describe how we are currently interfacing with other city-wide systems such as the Geo-Processing System, the Equipment Management System, Parts Inventory System and Personnel System. Some of the areas covered will be the integration of a Vehicle Allocation and Scheduling Algorithm into the Work Management System for our Paratransit Bus Service, and a unique feature called the System Dictionary. The System Dictionary adds the necessary flexibility that allows different areas of the City, such as Public Works, Water and Sewer Operations, Water Treatment Maintenance and Laboratory Operations, and Building Maintenance to use the same Work Management System.

The Work Management System is currently running on an IBM 4381 with a VM/VSE DOS operating system. Arlington is currently sharing information on its Work Management System with other cities. System specs and user manuals are available upon request.     

Observation of Unconventional Dynamics of Domain Walls in Uniaxial Ferroelectric Lead Germanate

Application of scanning probe microscopy techniques such as piezoresponse force microscopy (PFM) opens the possibility to re‐visit the ferroelectrics previously studied by the macroscopic electrical testing methods and establish a link between their local nanoscale characteristics and integral response. The nanoscale PFM studies and phase field modeling of the static and dynamic behavior of the domain structure in the well‐known ferroelectric material lead germanate, Pb₅Ge₃O₁₁, are reported. Several unusual phenomena are revealed: 1) domain formation during the paraelectric‐to‐ferroelectric phase transition, which exhibits an atypical cooling rate dependence; 2) unexpected electrically induced formation of the oblate domains due to the preferential domain walls motion in the directions perpendicular to the polar axis, contrary to the typical domain growth behavior observed so far; 3) absence of the bound charges at the 180° head‐to‐head (H–H) and tail‐totail (T–T) domain walls, which typically exhibit a significant charge density in other ferroelectrics due to the polarization discontinuity. This strikingly different behavior is rationalized by the phase field modeling of the dynamics of uncharged H–H and T–T domain walls. The results provide a new insight into the emergent physics of the ferroelectric domain boundaries, revealing unusual properties not exhibited by conventional Ising‐type walls.     

Interface Adaptation to Novice Older Adults’ Mental Models through Concrete Metaphors

Metaphors could be used to help older adults build mental models of Information and Communication Technology (ICT) applications and services and thereby reduce the number of interaction problems, but currently, metaphors generally are not tailored to these older adults, and their construction remains vague. Inspired by concrete icons, this study proposes concrete metaphors to help novice older adults understand ICT applications and services and retains their knowledge over time. A new communication application based on concrete metaphors was designed, developed, and comparatively tested against another application based on abstract metaphors over a period of 9 days. The results indicated that the application with concrete metaphors contributed to fewer perception and cognition errors, higher usage intention, higher satisfaction, and higher preference compared to the application with abstract metaphors. In addition, the advantage of concrete metaphors was lasting, unlike concrete icons. These findings indicated that concrete metaphors could be an icebreaker or stepping stone to draw novice older adults into the information society. To further increase the impact of concrete metaphors, representing real-world operations is an essential challenge.     

Re-utilization by perennial ryegrass (Lolium perenne L.) of labelled fertilizer sulphur incorporated in field-grown tops and roots of pasture plants added to soils

³⁵S-labelled gypsum fertilizer was incorporated under field conditions into pastures which were separated into white clover (Trifolium repens L.) and perennial ryegrass (Lolium perenne L.) tops and roots. These were added to four soils from improved and unimproved pastures. The re-utilization of labelled fertilizer sulphur (S) was assessed under growth cabinet conditions (20°C day, 13°C night, daylength 16 h, light intensity 120–170 lx) by growing perennial ryegrass plants for 23 weeks.Mean recoveries of labelled fertilizer S varied from 7 to 20% depending on soil type, form amount and kind of plant residue added. Greater recovery was obtained from clover roots (9.5–16.2%) than grass roots (6.7–12.5%), and from grass tops (13.1–19.7%) than clover tops (9.7–17.9%). These results are related to contents of labelled S, total S, C/N, C/S and N/S ratios in plant residues which also accounted for their relative rates of decomposition. Ground (< 1 mm) and chopped (3 mm) roots increased labelled fertilizer S recovery by about 30% compared with whole roots. Additions of unlabelled fertilizer S influenced the recovery of labelled fertilizer S. This effect depends on the amounts of labelled grass roots and unlabelled fertilizer added.The significance of the findings is discussed with the aid of results from previous field experiments conducted on these soils.     

Geospatial Reasoning Ability: Definition,Measurement and Validation

An understanding of geospatial reasoning ability (GRA) is essential to human–computer interaction research, as many recent consumer and commercial technologies require an ability to interpret complex geospatial data. Individuals, as well as government, commercial, and military organizations, use such technologies regularly. For instance, consumer technologies including online mapping services and in-vehicle navigation systems are increasingly prevalent. Business leaders rely on geospatial data when making strategic and operational decisions. Military strategists leverage geospatial systems during mission planning and battlefield operations. Although there has been research into the significance of user characteristics when making decisions using geospatial data, there is conflicting evidence on the impact of GRA on the decision-making process. This article suggests applying a multidimensional measure of GRA to facilitate a better understanding of such interactions. Furthermore, this article proposes a new measurement instrument developed through a rigorous scale development procedure and validated through an exploratory (n = 300) analysis.     

Some failure modes of four clinical bone cements

The fracture or failure behaviours of four commercial acrylic-based bone cements have been examined in tensile, bending and compression modes, and their mechanical properties are reviewed. It was found that Palacos R-40 bone cement had high radiopaque agent concentration, with high surface hardness. It exhibited a much lower bending strength and bending modulus compared with the other three bone cements (CMW1, CMW2000 and Simplex P). The textures of tensile fracture surfaces produced were similar for the four bone cements studied. The fracture surface was fragmented by crevices, which developed through the matrix and around large undissolved polymethylmethacrylate (PMMA) beads. Three bands with different features existed on the bending fracture surfaces, with an abrupt transition between them. It appears that the agglomerates of zirconium dioxide particles are implicated in Palacos R-40 bone cement fracture surface. The examination of compressive failed specimens revealed that a 'yielded crack band' existed across the transverse section. Plastic deformation resulted in the PMMA beads being squashed in the longitudinal direction and dilated in the transverse direction.