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Stabilization Challenges and Formulation Strategies Associated with Oral Biologic Drug Delivery Systems. - Advanced drug delivery reviews
Delivery of proteins to mucosal tissues of GI tract typically utilize formulations which protect against proteolysis and target the mucosal tissues. Using case studies from literature and the authors' own work, the in-process stability and solid state storage stability of biopharmaceuticals formulated in delivery systems designed for oral delivery to the GI tract will be reviewed. Among the range of delivery systems, biodegradable polymer systems for protection and controlled release of proteins have been the most studied; hence these systems will be covered in greater depth. These delivery systems include polymeric biodegradable microspheres or nanospheres that contain proteins or vaccines, which are designed to reduce the number of administrations/inoculations and the total protein dose required to achieve the desired biological effect. Specifically, this review will include a landscape survey of the systems that have been studied, the manufacturing processes involved, stability through the manufacturing process, key pharmaceutical formulation parameters that impact stability of the encased proteins, and storage stability of the encapsulated proteins in these delivery systems.Copyright Â© 2015 Elsevier B.V. All rights reserved.
Evaluation of Gallium Citrate Formulations against a Multidrug-Resistant Strain of Klebsiella pneumoniae in a Murine Wound Model of Infection. - Antimicrobial agents and chemotherapy
Skin and soft tissue infections (SSTIs) are a common occurrence in health care facilities with a heightened risk for immunocompromised patients. Klebsiella pneumoniae has been increasingly implicated as the bacterial agent responsible for SSTIs, and treatment can be challenging as more strains become multidrug resistant (MDR). Therefore, new treatments are needed to counter this bacterial pathogen. Gallium complexes exhibit antimicrobial activity and are currently being evaluated as potential treatment for bacterial infections. In this study, we tested a topical formulation containing gallium citrate (GaCi) for the treatment of wounds infected with K. pneumoniae. First, the MIC against K. pneumoniae ranged from 0.125 to 2.0 Î¼g/ml GaCi. After this in vitro efficacy was established, two topical formulations with GaCi (0.1% [wt/vol] and 0.3% [wt/vol]) were tested in a murine wound model of MDR K. pneumoniae infection. Gross pathology and histopathology revealed K. pneumoniae-infected wounds appeared to close faster with GaCi treatment and were accompanied by reduced inflammation compared to those of untreated controls. Similarly, quantitative indications of infection remediation, such as reduced weight loss and wound area, suggested that treatment improved outcomes compared to those of untreated controls. Bacterial burdens were measured 1 and 3 days following inoculation, and a 0.5 to 1.5 log reduction of CFU was observed. Lastly, upon scanning electron microscopy analysis, GaCi treatment appeared to prevent biofilm formation on dressings compared to those of untreated controls. These results suggest that with more preclinical testing, a topical application of GaCi may be a promising alternative treatment strategy for K. pneumoniae SSTI.Copyright Â© 2015 Thompson et al.
Human Nail Clippings as a Source of DNA for Genetic Studies. - Open journal of epidemiology
Blood samples have traditionally been used as the main source of DNA for genetic analysis. However, this source can be difficult in terms of collection, transportation, and long-term storage. In this study, we investigated whether human nail clippings could be used as a source of DNA for SNP genotyping, null-allele detection, and whole-genome amplification. From extracted nail DNA, we achieved amplicons up to a length of ~400 bp and >96% concordance for SNP genotyping and 100% concordance for null-allele detection compared to DNA derived from matched blood samples. For whole-genome amplification, OmniPlex performed better than Multiple Displacement Amplification with a success rate of 89.3% and 76.8% for SNP genotyping and null-allele detection, respectively. Concordance was ~98% for both methods. When combined with OmniPlex whole-genome amplification, human nail clippings could potentially be used as an alternative to whole blood as a less invasive and more convenient source of DNA for genotyping studies.
Gallium-based anti-infectives: targeting microbial iron-uptake mechanisms. - Current opinion in pharmacology
Microbes have evolved elaborate iron-acquisition systems to sequester iron from the host environment using siderophores and heme uptake systems. Gallium(III) is structurally similar to iron(III), except that it cannot be reduced under physiological conditions, therefore gallium has the potential to serve as an iron analog, and thus an anti-microbial. Because Ga(III) can bind to virtually any complex that binds Fe(III), simple gallium salts as well as more complex siderophores and hemes are potential carriers to deliver Ga(III) to the microbes. These gallium complexes represent a new class of anti-infectives that is different in mechanism of action from conventional antibiotics. Simple gallium salts such as gallium nitrate, maltolate, and simple gallium siderophore complexes such as gallium citrate have shown good antibacterial activities. The most studied complex has been gallium citrate, which exhibits broad activity against many Gram negative bacteria at âˆ¼1-5Î¼g/ml MICs, strong biofilm activity, low drug resistance, and efficacy in vivo. Using the structural features of specific siderophore and heme made by pathogenic bacteria and fungi, researchers have begun to evaluate new gallium complexes to target key pathogens. This review will summarize potential iron-acquisition system targets and recent research on gallium-based anti-infectives.Copyright Â© 2013 Elsevier Ltd. All rights reserved.
Effects of short-term exposure to air pollution on hospital admissions of young children for acute lower respiratory infections in Ho Chi Minh City, Vietnam. - Research report (Health Effects Institute)
There is emerging evidence, largely from studies in Europe and North America, that economic deprivation increases the magnitude of morbidity and mortality related to air pollution. Two major reasons why this may be true are that the poor experience higher levels of exposure to air pollution, and they are more vulnerable to its effects--in other words, due to poorer nutrition, less access to medical care, and other factors, they experience more health impact per unit of exposure. The relations among health, air pollution, and poverty are likely to have important implications for public health and social policy, especially in areas such as the developing countries of Asia where air pollution levels are high and many live in poverty. The aims of this study were to estimate the effect of exposure to air pollution on hospital admissions of young children for acute lower respiratory infection (ALRI*) and to explore whether such effects differed between poor children and other children. ALRI, which comprises pneumonia and bronchiolitis, is the largest single cause of mortality among young children worldwide and is responsible for a substantial burden of disease among young children in developing countries. To the best of our knowledge, this is the first study of the health effects of air pollution in Ho Chi Minh City (HCMC), Vietnam. For these reasons, the results of this study have the potential to make an important contribution to the growing literature on the health effects of air pollution in Asia. The study focused on the short-term effects of daily average exposure to air pollutants on hospital admissions of children less than 5 years of age for ALRI, defined as pneumonia or bronchiolitis, in HCMC during 2003, 2004, and 2005. Admissions data were obtained from computerized records of Children's Hospital 1 and Children's Hospital 2 (CH1 and CH2) in HCMC. Nearly all children hospitalized for respiratory illnesses in the city are admitted to one of these two pediatric hospitals. Daily citywide 24-hour average concentrations of particulate matter (PM) < or =10 microm in aerodynamic diameter (PM10), nitrogen dioxide (NO2), and sulfur dioxide (SO2) and 8-hour maximum average concentrations of ozone (O3) were estimated from the HCMC Environmental Protection Agency (HEPA) ambient air quality monitoring network. Daily meteorologic information including temperature and relative humidity were collected from KTTV NB, the Southern Regional Hydro-Meteorological Center. An individual-level indicator of socioeconomic position (SEP) was based on the degree to which the patient was exempt from payment according to hospital financial records. A group-level indicator of SEP was based on estimates of poverty prevalence in the districts of HCMC in 2004, obtained from a poverty mapping project of the Institute of Economic Research in HCMC, in collaboration with the General Statistics Office of Vietnam and the World Bank. Poverty prevalence was defined using the poverty line set by the People's Committee of HCMC of 6 million Vietnamese dong (VND) annual income. Quartiles of district-level poverty prevalence were created based on poverty prevalence estimates for each district. Analyses were conducted using both time-series and case-crossover approaches. In the absence of measurement error, confounding, and other sources of bias, the two approaches were expected to provide estimates that differed only with regard to precision. For the time-series analyses, the unit of observation was daily counts of hospital admissions for ALRI. Poisson regression with smoothing functions for meteorologic variables and variables for seasonal and long-term trends was used. Case-crossover analyses were conducted using time-stratified selection of controls. Control days were every 7th day from the date of admission within the same month as admission. Large seasonal differences were observed in pollutant levels and hospital admission patterns during the investigation period for HCMC. Of the 15,717 ALRI admissions occurring within the study period, 60% occurred in the rainy season (May through October), with a peak in these admissions during July and August of each year. Average daily concentrations for PM10, O3, NO2, and SO2 were 73, 75, 22, and 22 microg/m3, respectively, with higher pollutant concentrations observed in the dry season (November through April) compared with the rainy season. As the time between onset of illness and hospital admission was thought to range from 1 to 6 days, it was not possible to specify a priori a single-day lag. We assessed results for single-day lags from lag 0 to lag 10, but emphasize results for an average of lag 1-6, since this best reflects the case reference period. Results were robust to differences in temperature lags with lag 0 and the average lag (1-6 days); results for lag 0 for temperature are presented. Results differed markedly when analyses were stratified by season, rather than simply adjusted for season. ALRI admissions were generally positively associated with ambient levels of PM10, NO2, and SO2 during the dry season (November-April), but not the rainy season (May-October). Positive associations between O3 and ALRI admissions were not observed in either season. We do not believe that exposure to air pollution could reduce the risk of ALRI in the rainy season and infer that these results could be driven by residual confounding present within the rainy season. The much lower correlation between NO2 and PM10 levels during the rainy season provides further evidence that these pollutants may not be accurate indicators of exposure to air pollution from combustion processes in the rainy season. Results were generally consistent across time-series and case-crossover analyses. In the dry season, risks for ALRI hospital admissions with average pollutant lag (1-6 days) were highest for NO2 and SO2 in the single-pollutant case-crossover analyses, with excess risks of 8.50% (95% CI, 0.80-16.79) and 5.85% (95% CI, 0.44-11.55) observed, respectively. NO2 and SO2 effects remained higher than PM10 effects in both the single-pollutant and two-pollutant models. The two-pollutant model indicated that NO2 confounded the PM10 and SO2 effects. For example, PM10 was weakly associated with an excess risk in the dry season of 1.25% (95% CI, -0.55 to 3.09); after adjusting for SO2 and O3, the risk estimate was reduced but remained elevated, with much wider confidence intervals; after adjusting for NO2, an excess risk was no longer observed. Though the effects seem to be driven by NO2, the statistical limitations of adequately addressing collinearity, given the high correlation between PM10 and NO2 (r = 0.78), limited our ability to clearly distinguish between PM10 and NO2 effects. In the rainy season, negative associations between PM10 and ALRI admissions were observed. No association with O3 was observed in the single-pollutant model, but O3 exposure was negatively associated with ALRI admissions in the two-pollutant model. There was little evidence of an association between NO2 and ALRI admissions. The single-pollutant estimate from the case-crossover analysis suggested a negative association between NO2 and ALRI admissions, but this effect was no longer apparent after adjustment for other pollutants. Although associations between SO2 and ALRI admissions were not observed in the rainy season, point estimates for the case-crossover analyses suggested negative associations, while time-series (Poisson regression) analyses suggested positive associations--an exception to the general consistency between case-crossover and time-series results. Results were robust to differences in seasonal classification. Inclusion of rainfall as a continuous variable and the seasonal reclassification of selected series of data did not influence results. No clear evidence of station-specific effects could be observed, since results for the different monitoring stations had overlapping confidence intervals. In the dry season, increased concentrations of NO2 and SO2 were associated with increased hospital admissions of young children for ALRI in HCMC. PM10 could also be associated with increased hospital admissions in the dry season, but the high correlation of 0.78 between PM10 and NO2 levels limits our ability to distinguish between PM10 and NO2 effects. Nevertheless, the results support the presence of an association between combustion-source pollution and increased ALRI admissions. There also appears to be evidence of uncontrolled negative confounding within the rainy season, with higher incidence of ALRI and lower pollutant concentrations overall. Exploratory analyses made using limited historical and regional data on monthly prevalence of respiratory syncytial virus (RSV) suggest that an unmeasured, time-varying confounder (RSV, in this case) could have, in an observational study like this one, created enough bias to reverse the observed effect estimates of pollutants in the rainy season. In addition, with virtually no RSV incidence in the dry season, these findings also lend some credibility to the notion that RSV could influence results primarily in the rainy season. Analyses were not able to identify differential effects by individual-level indicators of SEP, mainly due to the small number of children classified as poor based on information in the hospitals' financial records. Analyses assessing differences in effect by district-level indicator of SEP did not indicate a clear trend in risk across SEP quartiles, but there did appear to be a slightly higher risk among the residents of districts with the highest quartile of SEP. As these are the districts within the urban center of HCMC, results could be indicative of increased exposures for residents living within the city center. (ABSTRACT TRUNCATED)
Biophysical characterization and conformational stability of Ebola and Marburg virus-like particles. - Journal of pharmaceutical sciences
The filoviruses, Ebola virus and Marburg virus, cause severe hemorrhagic fever with up to 90% human mortality. Virus-like particles of EBOV (eVLPs) and MARV (mVLPs) are attractive vaccine candidates. For the development of stable vaccines, the conformational stability of these two enveloped VLPs produced in insect cells was characterized by various spectroscopic techniques over a wide pH and temperature range. Temperature-induced aggregation of the VLPs at various pH values was monitored by light scattering. Temperature/pH empirical phase diagrams (EPDs) of the two VLPs were constructed to summarize the large volume of data generated. The EPDs show that both VLPs lose their conformational integrity above about 50Â°C-60Â°C, depending on solution pH. The VLPs were maximally thermal stable in solution at pH 7-8, with a significant reduction in stability at pH 5 and 6. They were much less stable in solution at pH 3-4 due to increased susceptibility of the VLPs to aggregation. The characterization data and conformational stability profiles from these studies provide a basis for selection of optimized solution conditions for further vaccine formulation and long-term stability studies of eVLPs and mVLPs.Copyright Â© 2011 Wiley-Liss, Inc.
Formulation and stabilization of Francisella tularensis live vaccine strain. - Journal of pharmaceutical sciences
Francisella tularensis live vaccine strain (F. tularensis LVS), a promising vaccine candidate for protection against F. tularensis exposure, is a particularly thermolabile vaccine and difficult to stabilize sufficiently for storage under refrigerated conditions. Our preliminary data show that F. tularensis LVS can be stabilized in the dried state using foam drying, a modified freeze drying method, with sugar-based formulations. The process was conducted under mild drying conditions, which resulted in a good titer retention following processing. The inclusion of osmolytes in the growth media resulted in an acceleration of growth kinetics, although no change in osmotolerance was observed. The optimized F. tularensis formulation, which contained trehalose, gelatin, and Pluronic F68 demonstrated stability for approximately 1.5 weeks at 37Â°C (i.e., time required for the vaccine to decrease in potency by 1 log(10) colony forming unit) and for 12 weeks at 25Â°C. At refrigerator storage condition (4Â°C), stabilized F. tularensis LVS vaccine exhibited no activity loss for at least 12 weeks. This stabilization method utilizes conventional freeze dryers and pharmaceutically approved stabilizers, and thus can be readily implemented at many manufacturing sites for large-scale production of stabilized vaccines. The improved heat stability of the F. tularensis LVS could mitigate risks of vaccine potency loss during long-term storage, shipping, and distribution.Copyright Â© 2011 Wiley-Liss, Inc.
Room temperature stabilization of oral, live attenuated Salmonella enterica serovar Typhi-vectored vaccines. - Vaccine
Foam drying, a modified freeze drying process, was utilized to produce a heat-stable, live attenuated Salmonella Typhi 'Ty21a' bacterial vaccine. Ty21a vaccine was formulated with pharmaceutically approved stabilizers, including sugars, plasticizers, amino acids, and proteins. Growth media and harvesting conditions of the bacteria were also studied to enhance resistance to desiccation stress encountered during processing as well as subsequent storage at elevated temperatures. The optimized Ty21a vaccine, formulated with trehalose, methionine, and gelatin, demonstrated stability for approximately 12 weeks at 37Â°C (i.e., time required for the vaccine to decrease in potency by 1log(10)CFU) and no loss in titer at 4 and 25Â°C following storage for the same duration. Furthermore, the foam dried Ty21a elicited a similar immunogenic response in mice as well as protection in challenge studies compared to Vivotifâ„¢, the commercial Ty21a vaccine. The enhanced heat stability of the Ty21a oral vaccine, or Ty21a derivatives expressing foreign antigens (e.g. anthrax), could mitigate risks of vaccine potency loss during long-term storage, shipping, delivery to geographical areas with warmer climates or during emergency distribution following a bioterrorist attack. Because the foam drying process is conducted using conventional freeze dryers and can be readily implemented at any freeze drying manufacturing facility, this technology appears ready and appropriate for large scale processing of foam dried vaccines.Copyright Â© 2011 Elsevier Ltd. All rights reserved.
Arabinoxylan rice bran (MGN-3) enhances the effects of interventional therapies for the treatment of hepatocellular carcinoma: a three-year randomized clinical trial. - Anticancer research
This study examined the efficacy of arabinoxylan rice bran (MGN-3) in conjunction with an interventional therapy (IT) for the treatment of hepatocellular carcinoma patients.A total of sixty-eight patients with hepatocellular carcinoma (stages I and II) participated in the study. Patients were randomized to receive IT (30 patients, control group) or IT+MGN-3 (38 patients), and randomly divided into two groups using a computer-generated randomization list. Patients and investigators were blinded. IT included transarterial oily chemoembolization (TOCE) or a combination of TOCE and percutaneous ethanol injection treatment (PEIT).Patients in the IT+MGN-3 group showed: (i) lower recurrence of the disease, 31.6% (12/38), as compared to 46.7% (14/30) for the control; (ii) higher survival after the second year, 35%, as compared to 6.7% for the control; (iii) significantly lower alpha-fetoprotein level, a 38% decrease (p = 0.0001), as compared to baseline value, while the control showed no significant change; and (iv) a significant decrease in tumor volume, in contrast to the control, which showed no significant change. When the results were analyzed according to each IT modality, MGN-3+IT sub-groups displayed a greater response to treatment, in every aspect examined, than the IT sub-groups alone. However, the patients in the MGN-3+TOCE+PEIT sub-group demonstrated greater reduction in AFP levels and longer survival time than the MGN-3+TOCE sub-group.MGN-3 in conjunction with IT may be useful for the treatment of hepatocellular carcinoma and warrants further investigation in multiple clinical trials.
Biophysical characterization of rotavirus serotypes G1, G3 and G4. - Human vaccines
The stability of attenuated virus vaccines has traditionally been assessed by a plaque assay to measure the virus's loss of replication competency in response to a variety of environmental perturbations. Although this method provides information regarding the impact of the vaccine formulation, it involves an empirical approach to evaluate stability. Biophysical studies on the other hand have the potential to provide insight into the mechanisms of inactivation of a viral vaccine in response to a variety of stressed conditions. Herein, we have employed a variety of spectroscopic techniques (i.e., circular dichroism, fluorescence spectroscopy and dynamic light scattering) for a comprehensive examination of the thermal stability of three live-attenuated human-bovine reassortant rotavirus strains (G1, G3 and G4) in the 5-8 pH range. The spectroscopic methods employed are not specific and response changes reflect an average change over the entire virus structure. The present work, however, suggests the utility of these methods in early formulation of rotaviral vaccines due to their ability to identify regions of marginal stability over which high throughput excipient screening assays can be designed. We have further shown that these methods are sufficiently sensitive to differentiate the stability of the three homologous G-subtypes differing only in the composition of their surface antigenic proteins. The data from these spectroscopic methods are also compared to biological activity using a tissue culture viral infectivity assay. Partial correlation between the structural alterations and losses in activity are observed, further suggesting the utility of biophysical studies in early formulation studies of rotavirus vaccines.
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