PubMed · 15611800
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Nick R Anthonisen. Asthma "control".. https://doi.org/10.1155/2004%2F678208
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PURPOSE: This study was performed to investigate the safety of alkylglycosides administered via the respiratory route and to compare the pulmonary absorption profiles of insulin administered as dry powder inhaler and inhaler solution. METHODS: The safety of a series of alkylglycosides with varying alkyl chain lengths was studied by measuring the enzymatic activities in the bronchoalveolar lavage (BAL) fluid of rat lungs. Pulmonary formulations of insulin plus octylmaltoside were administered either as solution or lyophilized dry powder to anesthetized rats, and absorption of insulin was assessed by measuring plasma insulin and glucose levels. The physical characterization of the dry powder formulation was performed using scanning electron microscope (SEM) and Fourier transform infrared spectrophotometer (FTIR). RESULTS: The BAL analysis showed that there was a gradual increase in the amount of lung injury markers released with the increase in the hydrophobic chain length of alkylglycosides. The pulmonary administration of lyophilized dry powder of insulin plus octylmaltoside or its solution counterpart showed that the bioavailability of powder formulation was about 2-fold higher than that of the formulation administered as solution. The SEM studies showed a subtle difference in the surface morphologies of formulation particles after lyophilization. FTIR data showed minor interactions between the peptide and excipients upon lyophilization. CONCLUSIONS: Of the alkylglycosides tested, octylmaltoside was least toxic in releasing lung injury markers. Octylmaltoside-based dry powder insulin formulations were more efficacious in enhancing pulmonary insulin absorption and reducing plasma glucose levels compared with the formulations administered as a solution.
Thinner inhalation causes toxic effects in a variety of organs, principally in the central nervous system. Some studies have shown oxidative stress effects of thinner inhalation, such as: activation of free radical processes, decrease of antioxidants, and oxidation products of proteins and lipids but not of DNA. The aim of this study is to investigate the effect of thinner inhalation on DNA. We used the comet assay in conjunction with the enzyme formamidopyrimidine glycoslyase (Fpg). Our results show a significant increase in Fpg-sensitive sites in DNA of lymphocytes from rats exposed to thinner fumes compared to lymphocytes from control rats (p < 0.05). Moreover, DNA damage detected with Fpg shows a high correlation with increased malondialdehyde (MDA) and decreased glutathione (GSH), two widely used biomarkers of oxidative stress. The most abundant base oxidation product found in DNA is 8-oxoguanine; it is the main substrate of Fpg and the most commonly used biomarker for oxidative DNA damage. This suggests that oxidative DNA damage is at least partly responsible for the DNA damage detected by Fpg. We propose the comet assay in combination with Fpg as a sensitive biomarker to monitor exposure to thinner inhalation. Limitations of this method are discussed.
Non-parametric procedures such as the Wilcoxon rank-sum test, or equivalently the Mann-Whitney test, are often used to analyse data from clinical trials. These procedures enable testing for treatment effect, but traditionally do not account for covariates. We adapt recently developed methods for receiver operating characteristic (ROC) curve regression analysis to extend the Mann-Whitney test to accommodate covariate adjustment and evaluation of effect modification. Our approach naturally extends use of the Mann-Whitney statistic in a fashion that is analogous to how linear models extend the t-test. We illustrate the methodology with data from clinical trials of a therapy for Cystic Fibrosis.