A pragmatic test of a simple calorimetric method for determining the fragility of some amorphous pharmaceutical materials

This study was performed in 36 healthy volunteers to define the relationship between plasma concentrations of partially oxidized low density lipoprotein (poxLDL), plasma glucose and insulin responses to oral glucose, and steady-state plasma glucose (SSPG) concentrations after a 180-minute infusion of somatostatin, insulin, and glucose. The concentration of poxLDL was estimated by determining the amount of conjugated dienes formed during in vitro LDL oxidation in the presence or absence of alanine. Under these conditions, the greater the in vitro antioxidant effect of alanine, the lower the amount of poxLDL that was present in plasma. The results demonstrated that plasma poxLDL concentration was significantly correlated with plasma glucose (r=.53, P<.001) and insulin (r=.43, P<.01) responses, SSPG concentrations (r=.53, P<.001), and plasma triglyceride (r=.42, P<.01) and HDL cholesterol (r=-.50, P<.002) concentrations. Furthermore, these relationships persisted when the data were corrected for differences in age, sex, body mass index, and the ratio of waist to hip girth. Of note, there was no correlation between poxLDL and LDL cholesterol concentration. When SSPG was entered along with age, sex, body mass index, and waist-to-hip ratio in a multiple regression model, SSPG alone was a significant prediction of poxLDL (r-=.37, P<.02). The addition of plasma glucose and insulin responses and triglyceride and HDL cholesterol concentrations increased the r2 to only .47. These results show that the amount of poxLDL in plasma is significantly correlated with insulin resistance (ie, SSPG) and its metabolic consequences.     

Benzoyl peroxide stability in pharmaceutical gel preparations

The storage stability of benzoyl peroxide in the presence of both individual and combined pharmaceutical gel ingredients was investigated. Benzoyl peroxide was quite unstable in the presence of nucleophilic agents and certain acidic substances. At both 30 and 40 degrees storage temperatures, benzoyl peroxide was destroyed rapidly (within 1 month) in the presence of ethanol and acidic chelating agents. The substitution of acetone for ethanol, the elimination of chelating agents, and the addition of sodium hydroxide to gel preparations markedly reduced degradation.     

Situation selection as a moderator of response consistency and stability.

Addressed the viability of introducing into the moderator variable literature a distinction between chosen and imposed situations in 2 studies with 62 undergraduates. In Study 1, the relation between recreational activity choices and selected personality traits and the stability of these choices over time was examined. In Study 2, the cross-situational consistency of affective and behavioral responses within self-rated chosen and imposed situations in Ss' everyday lives was examined. Situational choices were found to be relatively stable over a period of 9 mo and to be related in predictable ways to personality dispositions. Distinguishing between chosen and imposed situations produced differences in average cross-situational consistency coefficients, and differences between affective and behavioral responses were also found. Behavior was found to be more consistent within imposed situations. It is concluded that there is support for the claim that self-selection of individuals to situations moderates response consistency and stability. (42 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of mannitol crystallization on the stability and aerosol performance of a spray-dried pharmaceutical protein, recombinant humanized anti-IgE monoclonal antibody

We have examined the stability and aerosol performance of the pharmaceutical protein recombinant humanized anti-IgE monoclonal antibody (rhuMAbE25) spray dried with mannitol. The aerosol performance was measured by the fine particle fraction (FPF), and stability was assessed by the formation of soluble aggregates. When mannitol was added to the spray-dried rhuMAbE25 formulation, its ability to stabilize the protein leveled off above about 20% (w/w, dry basis). The FPF of the spray-dried formulations was stable during storage for rhuMAbE25 containing 10% and 20% mannitol, but the 30% formulation exhibited a dramatic decrease upon storage at both 5 degreesC and 30 degreesC, due to mannitol crystallization. We tested the addition of sodium phosphate to a 60:40 rhuMAbE25:mannitol (w:w) mixture, which otherwise crystallized upon spray drying and yielded a nonrespirable powder. The presence of sodium phosphate was successful in inhibiting mannitol crystallization upon spray drying and dramatically lowering the rate of solid-state aggregation. However, over long-term storage some crystallization was observed even for the phosphate-containing samples, concomitantly with increased particle size and decreased suitability for aerosol delivery. Therefore, the physical state of mannitol (i.e., amorphous or crystalline) plays a role both in maintaining protein stability and providing suitable aerosol performance when used as an excipient for spray-dried powders. Agents which retard mannitol crystallization, e.g., sodium phosphate, may be useful in extending the utility of mannitol as an excipient in spray-dried protein formulations.     

The effect of boundary selection on the stability and folding of the third fibronectin type III domain from human tenascin

Correct selection of domain boundaries is critical for structural analysis of single domains from multimodular proteins. Folding and stability studies of the third fibronectin type III domain from human tenascin (TNfn31-90) have shown that it is moderately stable (Delta G(D-N)(H2O) approximately 5 kcal mol-1) and folds with two-state kinetics. In an attempt to stabilize the protein, five domains were constructed with different combinations of extensions to the N- and C-termini. Thermal denaturation studies show that a specific two amino acid (Gly-Leu) extension at the C-terminus is primarily responsible for a significant increase in stability. The Delta Delta G(D-N)(H2O) of the Gly-Leu extension (TNfn3(1-92)) is 2.7 +/- 0.3 kcal mol-1. Refolding kinetics do not differ significantly, but unfolding is slowed 40-fold. Mutation of leucine 92 to alanine does not affect stability, indicating that the stability of the extension does not come from the packing of the leucine side chain. Hydrogen exchange data suggest that the extension adds new hydrogen bonds and strengthens existing hydrogen bonds in the C-terminal interaction with the A-B and E-F loops. Removal of a very small number of hydrogen bonds substantially increases the unfolding rate, a phenomenon which may be important in stress-relaxation of FNIII-containing muscle proteins such as titin. These experiments demonstrate the importance of a small number of additional long-range interactions in the overall formation of a compact independently folding beta-sheet module.     

Expansion and length-dependent fragility of CTG repeats in yeast

Expansion of DNA trinucleotide repeats (TNRs) is the causative mutation in a growing number of human genetic diseases. Large expansions of a CTG tract were obtained and shown by genetic and physical assays to be length-dependent sites of chromosome breakage in Saccharomyces cerevisiae. Deletion of RAD27, which encodes a nuclease involved in Okazaki fragment processing, caused length-dependent destabilization of CTG tracts and a substantial increase in expansion frequency. The genetic assay described here can be used to evaluate other factors that induce TNR expansion or chromosome fragility in humans.     

Graphic analysis of osmotic fragility of erythrocytes

A precise and highly reproducible method for analyzing the osmotic fragility of erythrocytes with a minute amount of blood (less than 10 mul) is described. The osmotic fragility curves are recorded with a coil planet centrifuge with accessories and a scanning photodensitometer. The recorded curves are transcribed by a DuPont Curve Resolver and their components are analyzed. Normal fragility curves obtained from healthy adults revealed slightly skewed Gaussian curves and they were resolved into several typical Gaussian components which differed according to the physical and clinical conditions of subjects. Each resolved component is supposed to correspond to the population of erythrocytes having a nearly identical osmotic fragility. The method is proved to be useful for the detection of altered membrane properties of erythrocytes in various diseases.     

Effect of storage of blood on the osmotic fragility of mammalian erythrocytes

The osmotic fragility of mammalian erythrocytes during blood storage was determined. Significant changes were observed in the fragility of goat, cattle, pig, mouse, rat and rabbit erythrocytes but not in sheep erythrocytes during the storage of blood for 24 hours at 10 degrees C.     

Karyotypic anomalies and chromosomal sites of increased fragility in colorectal cancer

Karyotypic structural aberrations in tumor cells and chromosome constitutive fragile sites (cFSs) in peripheral blood lymphocytes were studied in ten patients with colorectal adenocarcinoma Most chromosome breakpoints (38 out of 40, i.e., 95.0%) were shown to be located within cFSs in tumor cells. Expression of 24 out of 137 cFSs in patients was higher than that in healthy donors. Four of these cFSs (6q26, 7q36, 16q23, and 17q21), were involved in the formation of nonrandom tumor cell chromosome markers most characteristic of colorectal neoplasms. The frequency of damages induced within these sites was analyzed in each patient. Expression of 7q36, 16q23, and 17q21 was increased in blood cells of patients carrying specific chromosome rearrangements with the breakpoints within these sites. The association between nonrandom chromosome aberrations in tumor cells and cFSs in normal cells is discussed.     

稀土对硼铝硅酸盐玻璃形成及热膨胀性能的影响

探索了稀土掺杂Al2O3-B2O3-SiO2玻璃的形成区范围、稀土掺入量对玻璃形成区的影响,利用热膨胀的测试分析手段,分析了不同掺杂稀土氧化物对玻璃热膨胀性能的影响情况。结果表明:当稀土外掺含量逐渐增加时,玻璃形成区范围先扩大后缩小。稀土氧化物的引入可以有效的改善玻璃硼反常现象的发生,同时也有可能改变网络中间体氧化铝对玻璃网络的作用,即发生了从以网络外体为主变为以网络形成体为主的转变,玻璃的膨胀率降低。