A novel assessment system of toxicity and stability of CuO nanoparticles via copper super sensitive Saccharomyces cerevisiae mutants.

CuO nanoparticles (CuO-NPs) toxicity in organisms is contributed mainly through the copper uptake by both the ionic and nanoparticle form. However, the relative uptake ratio and bioavailability of the two different forms is not well known due to a lack of sensitive and effective assessment systems. We developed a series of both copper resistant and hyper sensitive Saccharomyces cerevisiae mutants to investigate and compare the effects of CuO-NPs and dissolved copper (CuCl2), on the eukaryote with the purpose of quantitating the relative contributions of nanoparticles and dissolved species for Cu uptake. We observed the toxicity of 10 mM CuO-NPs for copper sensitive strains is equal to that of 0.5 mM CuCl2 and the main toxic effect is most likely generated from oxidative stress through reactive oxygen species (ROS) production. About 95% CuO-NPs exist in nanoparticle form under neutral environmental conditions. Assessing the cellular metal content of wild type and copper transporter 1(CTR1) knock out cells showed that endocytosis is the major absorption style for CuO-NPs. This study also found a similar toxicity of Ag for both 10 mM Ag-NPs and 0.2 mM AgNO3 in the copper super sensitive strains. Our study revealed the absorption mechanism of soluble metal based nanomaterials CuO-NPs and Ag-NPs as well as provided a sensitive and delicate system to precisely evaluate the toxicity and stability of nanoparticles.

[Analysis of reliability and validity of the Chinese version of Nijmegen Cochlear Implant Questionnaire].

OBJECTIVE: To investigate the reliability and validity of the Chinese version of Nijmegen Cochlear Implant Questionnaire (NCIQ). METHODS: There were six subdomains: basic sound perception, advanced sound perception, speech production, self-esteem, activities and social Interactions. The cross-cultural adaptation measures were used to translate the NCIQ into its Chinese version. Ninety-four cochlear implant users no younger than 18 years old were included. Test-retest analysis was administered randomly to 30 users without significant changes in health and social status during a two weeks' interval between test and retest. RESULTS: (1) Reliability: test-retest reliability of the NCIQ was proved to be satisfactory. All domains had coefficients that exceeded 0.70 (P < 0.01). Except for the subdomain, speech production, whose Cronbach's α score was 0.560, other Cronbach's α scores were greater than 0.700. (2) VALIDITY: The correlation coefficients between overall NCIQ scores and the six subdomains were 0.620 - 0.810 (P < 0.01). There were weak or no correlations among the six subdomains. The evaluation of content validity by expert review showed the questionnaire had good content validity. NCIQ total scores in postlingually deafened users were significantly higher than those in prelingually deafened users (Z = 4.350, P = 0.000). This was also true for scores of the following subdomains:advanced sound perception (Z = 4.774, P = 0.000), speech production (Z = 4.416, P = 0.000), self-esteem (Z = 3.718, P = 0.000), activities (Z = 3.228, P = 0.001) and social interactions (Z = 3.001, P = 0.003). There was no significant difference between scores obtained from the two groups in the subdomain of basic sound perception (Z = 1.943, P = 0.052). CONCLUSIONS: The Chinese version of the NCIQ meets many psychometric criteria of a robust instrument. It possesses appropriate validity and good reliability, and can be used to measure the outcome of cochlear implant adults in China.

A computational model for the prediction of aqueous solubility that includes crystal packing, intrinsic solubility, and ionization effects.

The optimization of aqueous solubility is an important step along the route to bringing a new therapeutic to market. We describe the development of an empirical computational model to rank the pH-dependent aqueous solubility of drug candidates. The model consists of three core components to describe aqueous solubility. The first is a multivariate QSAR model for the prediction of the intrinsic solubility of the neutral solute. The second facet of the approach is the consideration of ionization using a predicted pKa and the Henderson-Hasselbalch equation. The third aspect of the model is a novel method for assessing the effects of crystal packing on solubility through a series of short molecular dynamics simulations of an actual or hypothetical small molecule crystal structure at escalating temperatures. The model also includes a Monte Carlo error function that considers the variability of each of the underlying components of the model to estimate the 90% confidence interval of estimation.

Discovery pharmaceutics--challenges and opportunities.

Most pharmaceutical companies are now evaluating compounds for druglike properties early in the discovery process. The data generated at these early stages allow upfront identification of potential development challenges and thus selection of the best candidates for lead nomination. Most often, lead nomination candidates are selected based on pharmacological and toxicological data. However, many drugs in development suffer from poor biopharmaceutical properties due to suboptimal physiochemical parameters. The poor biopharmaceutical properties often lead to extended timelines and a higher cost of developing the compounds. To avoid these problems and choose the best compounds from a biopharmaceutical perspective, physicochemical parameters such as solubility, lipophilicity, and stability need to be evaluated as early as possible. Furthermore, the preformulation approaches used to evaluate the compounds for their pharmacokinetic and toxicological properties need to be optimized. This minireview summarizes some of the parameters and approaches that can be used to evaluate compounds in the early stages of drug discovery.