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Development and evaluation of amphotericin B Loaded iron oxide nanoparticles for targeted drug delivery to systemic fungal infections
Get PDFA targeted nanotheronostic drug delivery system to diagnose and treat life threatening invasive fungal infections (IFIs) such as cryptococcal meningitis was designed, developed, characterized, and evaluated. To address the development processes, first, iron oxide nanoparticles (IONP) (34-40 nm) coated with bovine serum albumin (BSA), loaded and targeted with amphotericin B (AMB) (AMB-IONP) was formulated by applying a layer by layer approach. Several designs (A, B, C, D, & E) of AMB-IONP were developed and their physicochemical properties such as drug loading with HPLC method, particle size, poly dispersity index (PDI), and ζ-potential using dynamic light scattering (DLS) technique, morphology with transmission electronic microscopy (TEM), and in vitro drug release profile with dialysis method were evaluated. Second, uptake (with fluorescence microscopy and flow cytometry) and killing efficacy (with susceptibility testing) of AMB-IONP in fungal clinical isolates of Candida species were evaluated and compared with standard drug AMB deoxycholate (AMB-D) data. Third, the cellular uptake mechanisms with endocytosis inhibitors and intracellular trafficking using TEM for design D were evaluated in selected isolates. Fourth, a stable lyophilized AMB-IONP formulation was developed and was suitable for clinical trials.
A validated isocratic HPLC method was developed and validated for the quantitative determination of AMB. Design D was determined to be the lead formulation with drug loading of 13.6±6.9 of AMB/mg of IONP. The size, ζ-potential, and PDI for all formulation designs were found to be in an optimum range for a nanomedicine with ≤36 nm, ~ -20 mV, and ≤0.2, respectively. The TEM images confirmed that the nanoparticles were monodispersed and spherical in shape. The drug release profile indicated a burst release up to 3 hours for designs A and B, followed by a sustained drug release profile up to 72 hours. Designs C and D (with and without glutaraldehyde) also had a sustained drug release profile up to 72 hours. The major mechanisms of drug release from these formulations were determined to be Fickian and non-Fickian diffusion with first order and Higuchi kinetic models as best fit.
The cellular uptake profile for design D exhibited a time dependent uptake with maximum uptake at 0.5 and 4 hours for C. albicans and C. glabrata, respectively. All designs exhibited improved efficacy over AMB-D in the susceptibility testing conducted on clinical isolates of Candida. Design D was found to have an enhanced killing ability and was 16-25 fold more efficacious than AMB-D. An in vitro cellular association study found the uptake mechanism was energy dependent. An endocytosis inhibitor evaluation determined the major particle uptake pathway for C. albicans was lipid-raft mediated endocytosis, whereas for C. glabrata, it was clathrin-, caveolar-, and lipid-raft-mediated endocytosis.
TEM and confocal images provided evidence the AMB-IONP were localized at or near the cell wall and membrane wall and inside the cytoplasm, nucleus and endolysosomal vesicles for tested isolates. The lyophilized formulation of AMB-IONP was successfully prepared using an appropriate amount (1:16 to the weight IONP) of the of lyoprotectant, sucrose. A short term stability study of both formulations (lyophilized and aqueous dispersion) at 5°C and 25°C for up to two months showed the lyophilized form was stable.
In conclusion, a targeted nanotheronostic drug delivery system (AMB-IONP) was successfully designed, developed, characterized and evaluated as a potential drug product for IFIs treatment
Health Literacy Improves Health Care Quality
Get PDFA lack of knowledge about health literacy is a cause for quality healthcare concern as the world advances in health information technology. Many patients struggle to understand and navigate their health and well-being as a result of lack of understanding of the treatment plan due to low literacy skills. Several federal policy initiatives promote health literacy as the responsibility of the healthcare organization. Improving health outcomes through health literacy should be a commitment of healthcare organization through providing clear communication, simplified forms, assistance, and even follow-up calls. Three major initiatives will combat health literacy to include the Affordable Care Act; the National Action Plan to Improve Health Literacy of the Department of Health and Human Services; and the Plain Writing Act of 2010. These initiatives place strategic efforts on health literacy, health technology, and health disparities through patient-centered care in an effort to improve the quality of healthcare
The Effect of Background Music on the Visual Categorization of Printed Words in Normal Younger and Older Adults
Get PDFAim: Research has shown that background music, with and without vocal content, has a detrimental effect on cognitive task performance. Research has also shown a decline in processing speed as age increases. The present study seeks to answer the following questions: 1. Will background vocal music have any detrimental effects on performance of a visual semantic word categorization task? 2. Does age have any effect on performance of visual semantic word categorization in the presence of background music?
Participants: Participants consisted of 36 adult native speakers of English with normal speech and language divided in to two groups based on age, an older group (63-79 years) and a younger group (18-33 years). The younger group was recruited from the population of students of the University of Tennessee and the Knoxville community. The older group was recruited from the Knoxville Office on Aging and the Knoxville community.
Stimuli: Printed words were chosen from superordinate categories such as tools, utensils, animals, food, clothing, furniture, body parts, vehicles, toys, instruments, and insects. The auditory stimulus was Adele’s song “Someone Like You,” from the commercial CD recording. Instrumental recordings of the song were constructed using the music notation software program, Finale and sampled instruments.
Procedure: Participants performed a categorization task of printed words on the computer screen in the presence of background music. Participants’ reaction times and the accuracy of their responses were recorded by a software program, SuperLab Pro. The experiment was presented four times consecutively for four randomized auditory conditions consisting of 26 word sets per condition. A questionnaire was administered at the end of the final experiment.
Statistical Analysis: A mixed design 2x4 ANOVA was performed (between subjects factor – age group and within-subjects factor – condition) to test the main effects and/or interactions between groups and within groups. Paired sample T-tests were computed to test for comparisons within groups for any significant differences among conditions. Correlations and covariate analyses were performed for questionnaire data.
Results: The results did not indicate any significant effect of auditory condition on categorization task performance. Vocal music did not increase reaction times or decrease the accuracy of word categorization. On the other hand, a significant effect of age was found for reaction time and accuracy. Older adults performed significantly more slowly and less accurately than younger adults
Molecular Mechanisms Underlying Alcohol-Induced Cerebral Artery Smooth Muscle BK Channel Inhibition and Eventual Cerebral Vasoconstriction
Get PDFIntroduction and Rationale: Ethanol (EtOH) at concentrations obtained in circulation during moderate to heavy episodic drinking, such as during binge drinking (30-60 mM) causes cerebral vasoconstriction in many species, including humans. Using rodents as a model to study ethanolinduced cerebral artery constriction, our laboratory demonstrated that ethanol-induced cerebral artery constriction is due to drug-induced reduction of STOCs (Spontaneous Transient Outward Currents) in cerebral artery smooth muscle. In this tissue, STOCs result from the activity of large conductance, calcium-and voltage-gated potassium (BK) channels. Indeed, ethanol (50 mM) decreases the steady-state activity (NPo) of vascular myocyte BK channels leading to an increase in cerebral artery tone. In native tissues, functional BK channels are oligomers of four channel-forming slo1 subunits that are associated with small, accessory subunits (β1-4). β subunits do not form channels themselves but modify BK current phenotype, including its pharmacology. In particular, the vascular smooth muscle-abundant BK β1 subunit is required for ethanol to inhibit cerebral artery myocyte BK channels under physiological conditions of voltage and calcium. In contrast, the neuronally-predominant β4 subunit does not support this ethanol action. The molecular bases of ethanol-mediated inhibition of β1 subunit-containing BK channels and resulting cerebral vasoconstriction remain unknown.
Objective: Identify the BK β1 subunit regions and β1 subunit-dependent channel gating mechanisms underlying ethanol-induced inhibition of cerebral artery smooth muscle BK channel inhibition and eventual cerebral artery constriction.
Methods: Combination of recombinant DNA and other molecular biology in vitro approaches, patch-clamp electrophysiology, allosteric gating modeling, reversible permeabilization of arteries with cDNAs, and artery pressurization techniques.
Results: Ethanol sensitivity of slo1 current is dependent on the channel’s activating ion, i.e., Ca2+ i. Moreover, ethanol-induced modification of activity of slo1 (cbv1) and heteromeric cbv1+β1 BK channels is primarily due to modulation of calcium-driven gating: in particular, increase in Ca2+ i affinity; decrease in allosteric interaction between 1) RCK and voltage sensing domains and 2) RCKs and pore gate domains. Ethanol facilitation of channel inhibition is favored by β1-and β2 but not β3 or β4 subunits. Consistent with the involvement of calciumdependent mechanism, the former two drastically increase the channel’s apparent calcium sensitivity whereas the latter fail to do so. Transmembrane domains of BK-β1 subunit are essential for ethanol-mediated inhibition of β1-containing BK channels. In particular, the second transmembrane domain of β1 subunit is necessary for both inhibition of β1-containing BK channels and cerebral artery constriction evoked by ethanol.
Conclusion: BK β1 subunit TM2 enables ethanol-induced inhibition of β1-containing BK channels and cerebral artery constriction, with drug action on channel activity being dependent on modification of calcium-gating parameters
Optimization of Lead Spectinamide Compounds as Novel Anti-tuberculosis Agents with a Pharmacometric Approach
Get PDFIn an effort to combat the global Tuberculosis pandemic, Dr.Richard E. Lee and his group at St.Jude Children’s Research Hospital designed a novel series of anti-tuberculosis agents, spectinamides – semi-synthetic analogs of spectinomycin. Spectinamides are a potent inhibitor of mycobacterial ribosomes and overcome efflux mediated drug resistance in M. tb. Spectinamides have shown an excellent in vitro activity, which makes them well suited for further lead optimization and preclinical development. We hypothesized that through pharmacokinetic (PK) and pharmacodynamics (PD) model-based dosing optimization studies, we could strategically guide the selection and refinement of more potent and effective anti-TB spectinamides. Biopharmaceutical in vitro screening demonstrated that spectinamides in general have low plasma protein binding and are stable against hepatic microsomal metabolism. In vivo pharmacokinetic studies in rats revealed that the kidneys are the major route of elimination for spectinamides in their unchanged form. Radiolabeled biodistribution studies showed 84.7% of radioactivity accumulated 70% in urine, 12.6% in feces, and the remainder in the blood and other major organs. The unaccounted for residual 15.3% likely distributed into the epidermis and other surface tissue. In multiple-dose accumulation studies, the Cmax of radiolabeled compound after the 1st dose and the 8th dose of twice-daily dosing regimen was similar: 3.39µCi/mL and 3.55µCi/mL, suggesting no relevant accumulation of parent drug and metabolites. The concentration of radiolabeled compound was three times more in lungs and spleen as compared to whole blood, suggesting good tissue penetration. Macrophage uptake studies showed that Lee 1329, Lee1445 and Lee 1599 had significantly higher macrophage uptake than spectinomycin and streptomycin. Lee 1329 showed 6-fold and 2.2-fold higher uptake than streptomycin and spectinomycin, respectively. Based on the results of the in vitro experiments and preliminary PK/PD studies in rats, Lee 1599 was selected as the lead candidate compound. To predict PK/PD indices of antimicrobial efficacy, we performed model-based dosing optimization studies with Lee 1599. We used an in vitro PK/PD model system to simulate the rat PK conditions while evaluating antibacterial activities to predict effective dosing regimens for further in vivo efficacy studies. Our results have shown that Lee 1599 exhibits dose-dependent bactericidal effect. Lee 1599 showed up to 4-log reductions in bacterial counts at 100mg QD dosing. The PK/PD indices demonstrated that Lee 1599 elicits a concentration- and time-dependent killing with AUC/MIC as the optimal index. The model was put through numerical simulations to predict the effect of Lee 1599 in mice at various dosing regimens. The in vitro PK/PD simulated profile has suggested that high doses with frequent dosing intervals may demonstrate optimum in vivo efficacy. Consequently, we aimed to determine the pharmacodynamic interaction between Lee 1599 and existing anti-tuberculosis agent. We selected rifampicin as a model compound and applied a parametric approach to quantitatively assess the pharmacodynamic drug interaction between Lee 1599 and rifampicin. The three dimensional surface response assay demonstrated that there is an additive effect between both the agents as opposed to the conventional checkerboard assay, which suggested synergism between these agents. The results of surface response assay were validated using an in vitro PK/PD model for combination agents and in vivo efficacy trials, which showed an additive effect between Lee 1599 and rifampicin. Thus, quantitative assays such as the surface response assay seem to provide more reliable information on pharmacodynamic interactions as opposed to qualitative methods such as checkerboard assay. In conclusion, we have successfully supported the further development of spectinamides using a pharmacometric approach. We have identified a lead candidate compound Lee 1599 using an iterative PK/PD approach for its pre-clinical drug development. The application of PK/PD knowledge is essential for translating the in vitro screening assay findings to the in vivo stage, thus accelerating the drug development process. The results of the above studies can be used as a roadmap for the optimization of anti-infective agents in the early drug discovery and pre-clinical developmental phase
Managing Copy and Paste Functionality in the Electronic Health Record
Get PDFThe increased adoption of Electronic Health Records (EHR) has identified a significant need to develop tools to help providers maximize time spent documenting in the EHR. Copy and paste functionality, also known as carrying forward, cut and paste, and cloning, is one of many tools that can help providers save time and has been around longer than computers. A survey of thirteen Health Information Management (HIM) professionals responsible for HIMS functions within an acute care hospital in North Carolina was conducted. The survey response rate was 53%. The data gathered in this research study will add to HIM body of knowledge, in providing up-to-date data showing how copy and paste functionality is being addressed in acute care hospitals in North Carolina
Measuring Quality of Health Care in Type II Diabetes Mellitus Patients Using Certified Electronic Health Records
Get PDFGreat strides have been made in health care over the past six years after the implementation of the policy known as meaningful use by the Center of Medicare and Medicaid Services. Health care subsidies and monetary incentive programs were created for eligible professionals and critical area hospitals to encourage the use of certified electronic health records in an effort to improve quality care of all acute and chronically ill patients, as well as provide routine examinations for healthy individuals.
Patients diagnosed with type II diabetes mellitus were studied using a certified electronic health record system for compliance in physician ordered lab testing and follow-up visits with their primary care physician so as to confirm a positive effect on in the quality of patient health care. Diabetes mellitus is a disease which requires constant monitoring, thus creating an ideal patient study group. Research has confirmed that patient compliance significantly improves quality of health care outcomes; now it is time to determine that if the implementation of a certified electronic health record in the family practice setting improves patient compliance, thus improving quality of health care
HIPAA Violations on Social Media
Get PDFWith the rise of social media networks such as Facebook and Twitter, healthcare professionals and students pursing healthcare careers communicate, collaborate, and network on an array of websites and apps. With the use of social media, the users can reach a large audience in a matter of seconds, with this ease; users can transmit information and has presented challenges in the form of unauthorized disclosure of patient’s health information on social media sites. The purpose of this study is to see if the number of HIPAA violations increased due to the use of social media and what steps are healthcare companies taking to monitor HIPAA violations. I chose to use the survey research method to reach my participants. The population for my research is health information management professionals across the country employed at LifePoint Health. Web–based surveys with structured and unstructured questions, electronic databases, as well as Journal articles based on the subject of HIPPA violations on social media were used to access data. I used a statistical analysis to analyze the survey study data and interpretive analysis was used to identify patterns and relationships in the electronic databases and journal articles
Development of Oral Vaccines Against Lyme Disease
Get PDFLyme Disease, caused by the spirochete Borrelia burgdorferi, is the most common vector-borne disease in the United States and Europe. If left untreated, it can lead to permanent damage to the nervous and musculoskeletal systems. In some cases, patients that receive the recommended antibiotic therapy develop a debilitating health condition associated with substantial health care costs. Despite current preventive measures, the incidence and the geographic distribution of Lyme Disease continues to increase. Recent estimates from CDC suggest that the true number of cases of Lyme Disease in the US is approximately 300,000 per year. Yet, there is currently no vaccine available for human use, and thus novel strategies to diminish the risk of human exposure to Borrelia burgdorferi are of utmost importance. In an effort to address this need, we developed and tested an array of oral vaccine candidates based on recombinant E. coli that express B. burgdorferi’s OspC type K, OspB, BBK32, and Ixodes scapularis Salp15 and Salp25. Only oral immunization with live E. coli expressing OspC K induced systemic immune responses characterized by high levels of OspC K-specific IgG antibodies in sera as well as IgA antibodies in mucosal secretions, obtained from C3H-HeN mice. Vaccine efficacy studies demonstrated that OspC K-vaccinated mice were not protected from infection when challenge was performed via the natural route of disease transmission using ticks infected with multiple strains of B. burgdorferi, as assessed by the presence of antibodies to B. burgdorferi coupled with positive cultures and f B. burgdorferi is transmitted via ticks harboring also other types of OspCs. Our positive q-PCR results from bladder, heart and ear. Most importantly, we have shown that antibodies specific to OspC type K do not protect mice from infection when the homologous type of B. burgdorferi is transmitted via ticks harboring also other types of OspCs. Our findings are both critical and relevant, and should be considered in future studies involving the design and development of OspC-based vaccines against Lyme Disease
Scoliosis Analog Model for the Evaluation of Bracing Technology
Get PDFThoracolumbar braces are commonly used to treat Adolescent Idiopathic Scoliosis (AIS). Braces serve to reduce and prevent progression of the spinal curve by applying corrective forces. The magnitude and direction of these corrective forces applied by the brace to the spine remain unknown. Additionally the brace fitting process involves making alterations to the brace that affect its corrective force capacity. The objective was to design and validate an analog model of a mid-thoracic single curve scoliotic deformity for quantifying structural properties of the brace and the force response of the brace on the spine. This model was used to investigate the effects of strap-related brace design alterations. Additionally, the model was customized and demonstrated to be representative of a clinical case study.
A novel mechanically-equivalent analog model of the AIS condition was designed and developed to simulate up to 40 degrees of spinal correction. The linkage-based model was used in conjunction with a biorobotic testing platform to test a scoliosis brace. Measurements of the force components applied to the model and angular displacement of the linkage assembly were used to calculate the brace structural stiffness properties. The brace was tested using two types of straps (Velcro and buckle) applied in various configurations and compared to an unconstrained configuration and rigidly constrained configuration to demonstrate the capacity of the model to study brace design alterations.
Calculated stiffness was expressed as a resistive force relative to the angular change of the linkage system. Addition of either strap type significantly increased the stiffness values relative to the unconstrained configuration. An optimal brace radial stiffness was achieved with three Velcro straps, i.e., there was no significant stiffness gained by adding a fourth strap. For the case of the buckle straps, no significant stiffness gain occurred when more buckle straps were added.
Structural properties provide a means to compare bracing technology and better understand design features. The testing of design alterations, i.e. variable strap configurations, show a measureable difference in brace force response and structural properties between each configuration. Also, interpretation of the measured force components revealed that the brace applied inward and upward forces to the spine.
A novel scoliosis analog model and testing assembly were developed to provide first time measures of the forces applied to the spine by a thoracolumbar brace. In addition to quantifying brace structural properties, this test assembly could be used as a design and testing tool for scoliosis brace technology