NANOPARTICLE AGGLOMERATES FOR PULMONARY DRUG DELIVERY

The Pulmonary route has been traditionally used to treat diseases of the respiratory tract. However, important research within the last two decades have shown that in addition to treating local diseases, a wide range of systemic diseases can be treated by delivering drugs to the lungs. The recent FDA approval to market Exubera, an inhalable form of insulin developed by Pfizer, to treat Diabetes, may just be the stepping stone that the pharmaceutical industry needs to market other drugs to treat systemic diseases via the lungs. However, this technology still needs repeated drug doses to control glucose levels, as the inhaled drug is cleared rapidly. Technologies have been developed where inhaled particles are capable of controlled release of drug from the lungs. An important feature of these technologies is the large geometric size of the particles that makes it difficult for the lung macrophages to clear these particles, which results in longer residence times for the particles in the lungs. Owing to the porosity, these particles have lower densities making them deliverable to the deep lungs. However, no modulation of drug release can be achieved with these technologies when more drug release may be required. This additional requirement can only be assuaged by additional dosing of the drug formulation, which can have undesirable effects due to excess loading of excipients in the lungs. In an attempt to bring about modulation of release from long residence time particles, a novel concept was developed in our laboratory that has been termed as the Agglomerated Vesicle Technology (AVT). Liposomes with encapsulated drug were agglomerated using well known cross linking chemistries to form agglomerates in the micron sized range. The large particles exhibited aerodynamic sizes in the respirable size range with minimal damage to the particles upon nebulization. By breaking the cross links between the liposomes with a cleaving agent, it was anticipated that triggered release of drug from the AVT particles could be achieved. In vivo studies done in healthy rabbits showed that post-administration modulation of drug release is possible from the AVT particles after the introduction of the cleaving agent. This study has important implications for the future development of this technology, where the AVT particles can be made “sensitive” to the product of disease. It is envisaged that a single dose of AVT containing the appropriate drug when administered to the lungs would maintain drug levels at a controlled rate over an extended period of time. When the need for more drug arises, the product of the disease would trigger the AVT particles to release more drug as needed to control the condition, thus eliminating the need for repeated drug doses and improved compliance amongst patients.

Clinical, microbiological, and immunological markers of gingival and periodontal disease induction and progression

The potential impact of periodontal disease, a suspected risk factor for systemic diseases, presents challenges for health promotion and disease prevention strategies. This study examined clinical, microbiological, and immunological factors in a disease model to identify potential biomarkers that may be useful in predicting the onset and severity of both inflammatory and destructive periodontal disease. This project used an historical cohort design based on data obtained from 47 adult, female nonhuman primates followed over a 6-year period for 5 unique projects where the ligature-induced model of periodontitis was utilized. Standardization of protocols for sample collection allowed for comparison over time. Bleeding and pocket depth measures were selected as the dependent variables of relevance to humans based upon the literature and historical observations. Exposure variables included supragingival plaque, attachment level, total bacteria, black-pigmented bacteria, Gram-negative and Gram-positive bacteria, total IgG and IgA in crevicular fluid, specific IgG antibody in both crevicular fluid and serum, and IgG antibody to four select pathogenic microorganisms. Three approaches were used to analyze the data from this study. The first approach tested for differences in the means of the response variables within the group and among longitudinal observations within the group at each time point. The second approach examined the relationship among the clinical, microbiological, and immunological variables using correlation coefficients and stratified analyses. Multivariable models using GEE for repeated measures were produced as a predictive description of the induction and progression of gingivitis and periodontal disease. The multivariable models for bleeding (gingivitis) include supragingival plaque, total bacteria and total IgG while the second also contains supragingival plaque, Gram-positive bacteria, and total IgG. Two multivariable models emerged for periodontal disease. One multivariable model contains plaque, total bacteria, total IgG and attachment level. The second model includes black-pigmented bacteria, total bacteria, antibody to Campylobacter rectus, and attachment level. Utilization of the nonhuman primate model to prospectively examine causal hypotheses can provide a focus for human research on the mechanisms of progression from health to gingivitis to periodontitis. Ultimately, causal theories can guide strategies to prevent disease initiation and reduce disease severity. ^

Evaluation of risk factors for long term changes in refractive error among adult patients at a Dallas Texas private setting A retrospective chart-review study

Background. Over 39.9% of the adult population forty or older in the United States has refractive error, little is known about the etiology of this condition and associated risk factors and their entailed mechanism due to the paucity of data regarding the changes of refractive error for the adult population over time.^ Aim. To evaluate risk factors over a long term, 5-year period, in refractive error changes among persons 43 or older by testing the hypothesis that age, gender, systemic diseases, nuclear sclerosis and baseline refractive errors are all significantly associated with refractive errors changes in patients at a Dallas, Texas private optometric office.^ Methods. A retrospective chart review of subjective refraction, eye health, and self-report health history was done on patients at a private optometric office who were 43 or older in 2000 who had eye examinations both in 2000 and 2005. Aphakic and pseudophakic eyes were excluded as well as eyes with best corrected Snellen visual acuity of 20/40 and worse. After exclusions, refraction was obtained on 114 right eyes and 114 left eyes. Spherical equivalent (sum of sphere + ½ cylinder) was used as the measure of refractive error.^ Results. Similar changes in refractive error were observed for the two eyes. The 5-year change in spherical power was in a hyperopic direction for younger age groups and in a myopic direction for older subjects, P<0.0001. The gender-adjusted mean change in refractive error in right eyes of persons aged 43 to 54, 55 to 64, 65 to 74, and 75 or older at baseline was +0.43D, +0.46 D, -0.09 D, and -0.23D, respectively. Refractive change was strongly related to baseline nuclear cataract severity; grades 4 to 5 were associated with a myopic shift (-0.38 D, P< 0.0001). The mean age-adjusted change in refraction was +0.27 D for hyperopic eyes, +0.56 D for emmetropic eyes, and +0.26 D for myopic eyes.^ Conclusions. This report has documented refractive error changes in an older population and confirmed reported trends of a hyperopic shift before age 65 and a myopic shift thereafter associated with the development of nuclear cataract.^