Design of drug delivery strategies based on well-stirred experiments

Drugs are generally administered to the human body via injections (IV) or through other paths such as the buccal, nasal routes. The main consideration when designing a medication schedule is to maintain a therapeutic level of the drug in the body during the course of treatment. To achieve this goal, when IV drug therapy is selected, particular importance has to given to the dose to be injected and how to maintain the concentration of the pharmaceutical active ingredient (API) in the body between a Minimum Toxic Concentration (MTC) and a Minimum Effective Concentration (MEC). This therapeutic range varies with the drug and is designed so that the patient takes full benefit of the treatment while keeping potential risks or side effects to a minimum. The aim of this thesis is to design drug administration protocols based on well- stirred vessel experiments that mimic one- and two-compartment pharmacokinetic models. A one-compartment model assumes that drug is evenly distributed in the body, which is represented by a beaker with an inlet and an outlet stream. In a two- compartment model, drug is distributed between the central and peripheral vessels. Only bolus and constant-rate infusion are considered in this study. Mathematical models are used to estimate the pharmacokinetic parameters and to derive administration strategies to be tested experimentally. Results show that the well-stirred vessel captures the behavior of one- and two-compartment models very well. The time-concentration profiles of a tracer in the compartments are functions of the kinetic parameters

Comparison of 19mm Superpave and Marshall Base II mixes in West Virginia

The Superior Performing Asphalt Pavements (Superpave(TM)) asphalt concrete mix design method was developed through Strategic Highway Program (SHRP) in 1993. With the introduction of Superpave mix design, the Marshall method of mix design is becoming obsolete for highway pavements. Superpave implementation varies by state. The WVDOH has implemented Superpave on all National Highway System projects since 1997. The decision regarding implementation of Superpave for low volume roads in WV is still under review.;The primary objective of this research work was to compare the 19mm Superpave and Base II Marshall design mixes in WV to supplement information required for WVDOH to make a suitable decision regarding the implementation of Superpave for low volume roads.;The Marshall and Superpave methods were compared by preparing similar mix design with each method. The mix designs from each method were cross-compared with the conclusion that mixes developed under one method meet the criteria of the other method. In addition, the Asphalt Pavement Analyzer (APA) was used to evaluate rutting performance of gyratory compacted samples in the laboratory. The statistical analysis of rut depth results indicated there is not enough evidence to conclude there is a significant difference between the Marshall and Superpave mix design methods. It can be concluded that for the materials evaluated in this research, the Marshall and Superpave methods produce interchangeable results

Modeling Volume Change Due to Intercalation Into Porous Electrodes

Electrochemical devices (batteries, fuel cell) are expected to play a vital role in the future of energy consumption for various purposes ranging from house hold usage to space exploration. Research is being conducted on various aspects so as to improve the design and operating range of these devices and one of the primary focuses is the porous electrode. It has been reported that significant volume change can occur during electrode processes, within the porous electrodes and depending on the material it can be as high as, but not limited to 300%. These large volume changes along with product formation in pores can cause severe mechanical and performance degradation. However, prediction of stresses generated inside the electrode is highly empirical. Predictive models could give crucial insight into design parameters. Here we have formulated a continuum presentation of the porous material which combines mechanics of the solid phase of the porous material with the dependence of porosity on stress, as in rock-mechanics. In this new model, the deformation of the porous electrode material is characterized by its compressibility. Using the analogy between thermal stress-strain relationships and stress-strain relationship for existing concentration gradients, a constitutive law for the volumetric strain of the electrode during intercalation is developed, facilitating the prediction of volume and porosity change from fundamental material properties. The model is general and in conjunction with appropriate boundary and initial conditions, can be used to predict the volume and porosity change of any electrode during operation

The Nlrp3 inflammasome is critical for aluminium hydroxide-mediated IL-1β secretion but dispensable for adjuvant activity

Aluminum hydroxide (alum) is the most widely used adjuvant in human vaccines, but the immune mechanisms that are activated by alum remain poorly understood. Alum has recently been shown to promote caspase-1 activation and IL-1β secretion, but the cellular pathways involved remain elusive. Here we report that the release of IL-1β triggered by alum is abrogated in macrophages deficient in the NLR family, pyrin domain containing 3 (Nlrp3) protein and the apoptosis-associated speck-like protein containing a caspase recruitment domain (Asc) but not the NLR family, CARD domain containing 4 (Nlrc4) protein. The requirement of the Nlrp3 inflammasome was specific for IL-1β in that secretion of TNF-α was independent of Nlrp3 or Asc. Consistently, processing of pro-caspase-1 induced by alum was abolished in macrophages lacking Nlrp3 or Asc. Unlike caspase-1 processing and IL-1β secretion triggered by LPS, alum-mediated activation of the inflammasome did not require exogenous ATP. Importantly, induction of IgG production against human serum albumin by alum was unimpaired in mice deficient in Nlrp3. These results indicate that alum induces IL-1β via the Nlrp3 inflammasome but this activity is dispensable for alum-mediated adjuvant activity. See accompanying article: http://dx.doi.org/10.1002/eji.200838648Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/60465/1/2085_ftp.pd

Reactive oxygen species regulate caspase-11 expression and activation of the non-canonical NLRP3 inflammasome during enteric pathogen infection

Enteropathogenic and enterohemorrhagic bacterial infections in humans are a severe cause of morbidity and mortality. Although NOD-like receptors (NLRs) NOD2 and NLRP3 have important roles in the generation of protective immune responses to enteric pathogens, whether there is crosstalk among NLRs to regulate immune signaling is not known. Here, we show that mice and macrophages deficient in NOD2, or the downstream adaptor RIP2, have enhanced NLRP3-and caspases-11-dependent non-canonical inflammasome activation in a mouse model of enteropathogenic Citrobacter rodentium infection. Mechanistically, NOD2 and RIP2 regulate reactive oxygen species (ROS) production. Increased ROS in Rip2-deficient macrophages subsequently enhances c-Jun N-terminal kinase (JNK) signaling resulting in increased caspase-11 expression and activation, and more non-canonical NLRP3-dependant inflammasome activation. Intriguingly, this leads to protection of the colon epithelium for up to 10 days in Rip2-deficient mice infected with C. rodentium. Our findings designate NOD2 and RIP2 as key regulators of cellular ROS homeostasis and demonstrate for the first time that ROS regulates caspase-11 expression and non-canonical NLRP3 inflammasome activation through the JNK pathway

Animal Models of Colitis-Associated Carcinogenesis

Inflammatory bowel disease (IBD) is a group of chronic inflammatory disorders that affect individuals throughout life. Although the etiology and pathogenesis of IBD are largely unknown, studies with animal models of colitis indicate that dysregulation of host/microbial interactions are requisite for the development of IBD. Patients with long-standing IBD have an increased risk for developing colitis-associated cancer (CAC), especially 10 years after the initial diagnosis of colitis, although the absolute number of CAC cases is relatively small. The cancer risk seems to be not directly related to disease activity, but is related to disease duration/extent, complication of primary sclerosing cholangitis, and family history of colon cancer. In particular, high levels and continuous production of inflammatory mediators, including cytokines and chemokines, by colonic epithelial cells (CECs) and immune cells in lamina propria may be strongly associated with the pathogenesis of CAC. In this article, we have summarized animal models of CAC and have reviewed the cellular and molecular mechanisms underlining the development of carcinogenic changes in CECs secondary to the chronic inflammatory conditions in the intestine. It may provide us some clues in developing a new class of therapeutic agents for the treatment of IBD and CAC in the near future

Innate Immune Recognition of mtDNA—An Undercover Signal?

In addition to their roles in cellular metabolism and apoptosis, mitochondria function as signaling platforms in the innate immune response. In Nature, West et al. (2015) demonstrate that mitochondrial stress triggers a type I interferon response and confers viral resistance via release of mtDNA and activation of the cGAS–STING pathway