No description available.

No description available.

This thesis explores the effectiveness of the Food and Drug Administration’s implementation of Breakthrough Therapy Designation (BTD), focusing on the low number of approval rates and repercussions of BTD for the development of new drugs for patients suffering serious life threatening illnesses. BTD, as an expedited review process, shows potential for improvement in its guidelines for necessary qualifications for BTD. Cutting costs, through a shortening in development time, and raising profits, through first mover status of new to market drugs, BTD is regarded by pharmaceutical executives as a tool to insure not only return on investment but also the rewards that accompanies a profitable blockbuster drug. Lessons learned from activism from 1980’s HIV/AIDS crisis show how advocates and “activist-experts” can rebalance and refocus more attention on the necessary beneficence for patients. A policy stipulation that insures all members: corporate, regulatory, and patient advocate, sit together at the decision making table will insure a more balanced discussion in regards to drug development.

Pain from bone metastases is multifaceted with clinical descriptors including ongoing pain, hypersensitivity to external stimuli and intermittent episodes of breakthrough pain characterized as a sudden and abrupt onset of severe pain on a background of well-controlled pain. Moreover, cancer-induced bone pain remains inadequately managed due to a myriad of side effects associated with the current pain relieving regimens, which primarily rely on administration of opiates. Despite advances made in cancer therapeutics, these patients experience an inferior quality of life with incapacitating pain with limited daily activities. Development of long-term novel, non-opiate mechanism-based therapeutics with limited side effects is considered beneficial in elevating the patients' quality of life. First part of this dissertation encompasses the role of p38 MAPK in a mouse model of cancer-induced bone pain in which breast cancer cells were injected and sealed into the femur. Our data demonstrated that both acute and prolonged inhibition of p38 MAPK blocked cancer-induced spontaneous pain but had no effect on the evoked pain indicating important differences in mechanisms mediating ongoing pain as opposed to evoked pain. Undermanaged control of breakthrough pain is attributed to poor understanding of underlying mechanisms and how they may differ from ongoing pain due, in part, to lack of a pre-clinical model in which these mechanisms can be studied. We have established a rat model of cancer-induced bone pain to examine ongoing pain and pain relief using conditioned place preference paradigm as well as breakthrough pain using palpation-induced conditioned place aversion. We have shown that while peripheral afferent input from the tumor-bearing tibia mediates cancer-induced ongoing pain and initiation of breakthrough pain, it does not contribute to the maintenance of breakthrough pain. These data suggest that molecular targets mediating these two mechanisms may be different. This hypothesis was confirmed by our findings in this model that acute blockade of interleukin-6 blocked movement-evoked breakthrough pain in tumor-bearing rats, but failed to block tumor-induced ongoing pain. Hence, we provide a platform to manipulate treatments that can be given alone or in combination with opiates in such a way that patients receive adequate control of breakthrough pain.

Aim: To investigate the relationship between effective fentanyl sublingual spray (FSS) doses for breakthrough cancer pain (BTCP) and around-the-clock (ATC) transdermal fentanyl patch (TFP). Methods: Adults tolerating ATC opioids received open-label FSS for 26 days, followed by a 26-day double-blind phase for patients achieving an effective dose (100-1600 mu g). Results: Out of 50 patients on ATC TFP at baseline, 32 (64%) achieved an effective dose. FSS effective dose moderately correlated with mean TFP dose (r = 0.4; p = 0.03). Patient satisfaction increased during the study. Common adverse events included nausea (9%) and peripheral edema (9%). Conclusion: FSS can be safely titrated to an effective dose for BTCP in patients receiving ATC TFP as chronic cancer pain medication. ClinicalTrials.gov identifier: NCT00538850

It is estimated that 9-14% of children from birth to age 5 experience social and emotional problems that may significantly affect their ability to learn later in life and students of any age may experience an array of problems resulting in difficulty learning. Although interventions are available to address these issues within the school context, government funding for programs is often limited to those that are evidence based. Student Assistance Programs (SAPs) address a variety of barriers to learning but many are not supported by empirical evidence. The purpose of the study was to determine if Breakthrough, a specific SAP, had a significant effect on the dependent variables of grade point average, attendance, and behavioral referrals among N = 727 public school students in Grades 9-12. The independent variables were completion or noncompletion of the program, time, and grade level. This quantitative study used a systems perspective, nonequivalent control group design. The statistical analyses performed were a mixed ANOVA and a generalized estimating equation. The interaction of treatment, time, and grade level were found to be significant on attendance, and the interaction between treatment and time on was found to be significant for attendance. The main effect of time was found to be significant on grade point average, attendance, and behavioral referrals. The main effect of treatment was found to be significant on number of behavioral referrals. Increasing the types of supports for school-aged students may bring positive social change by allowing for higher academic achievement and by intervening with issues that may follow students into adulthood such as mental illness and substance abuse.

Disposable filtering facepiece respirators (FFRs) include a wide range of products that may be certified or non-certified. Many of these respirators are being produced with activated carbon claiming nuisance level organic vapor (OV) relief. OV includes a wide range of volatile organic compounds (VOCs) which have been linked to major and minor health discomfort such as headaches, upper extremity discomfort, nausea, respiratory irritation, asthma nervous system complications, hearing loss, cancer, and death. Common industries that have been identified that may expose employees to nuisance level OV, resulting in minor symptoms, include beautician salons, dry cleaning operations, and pesticide applications. FFRs with activated carbon (FFR-AC) may provide a more convenient alternative for reusable respirators which could also protect employees from OV exposure. This study investigated the adsorption capabilities of one certified respirator (3M) and two alternatively designed respirators (RZ Hunting Mask, Surgical Mask) with activated carbon filtering media. The three FFRs were tested to determine the 50% breakthrough time for two hydrocarbons and one non-carbon-based vapor. 50% breakthrough was chosen because we felt that reducing nuisance level exposures by half would still be protective. Non-certified respirators were exposed to 15 parts per million (ppm) and 50 ppm for all three vapors. Concentrations of 15 ppm and 50 ppm were standardized to achieve similar mass per time exposures across all contaminants and because these values represented the range of nuisance level exposure documented in literature. The 3M respirator was exposed to 15 and 50 ppm of acetone and ammonia, and perchloroethylene was evaluated at 50 ppm. Perchloroethylene was not evaluated at 15 ppm because breakthrough was longer than 8 hours. 3M respirators were also evaluated at 95% relative humidity using 50 ppm of acetone, ammonia, and perchloroethylene. The total number of trials was 43 (n=43). These contaminants and concentrations were chosen based on published data on occupational exposures. The non-certified respirators, (RZ Hunting Mask and Surgical Mask) , were ineffective for all vapors and offered less than 10 minutes of protection before 50% breakthrough occurred. Respirators performed poorly, when exposed to ammonia, with breakthrough less than 5 mins at 50 ppm and 10 minutes at 15 ppm. The 3M respirator had the longest breakthrough times for all trials. Acetone breakthrough occurred at 121 minutes for 50 ppm and 233 minutes at 15 ppm. Perchloroethylene took over 400 minutes to achieve 50% breakthrough at 50 ppm. When acetone at 50 ppm and perchloroethylene at 50 ppm were evaluated with 95% R.H. breakthrough times decreased to 39 and 144 minutes respectively, a nearly 70% decrease in time for both vapors. The results of this study show that non-certified respirators advertised as nuisance level relief may not offer protection for OV. Certified respirators show much more promise, but their performance is highly dependable upon the characteristics of the vapor and environment the respirators are being used in. Additional research is needed to increase our understanding of FFR-ACs performance under more conditions.

>Magister Scientiae - MSc / The current study aimed at providing groundwater recharge estimates in a fractured rock aquifer environment that is occupied by pine plantation and indigenous forests in order to improve the understanding of the effect of pine plantation forests on recharge. This was based on the argument that for the trees to affect recharge, they do not necessarily need to tap directly from the saturated zone, as vegetation may indirectly affect groundwater recharge by interception and abstracting the infiltrating water in the vadose zone before reaching the water table. The study was conducted along the Southern Cape coastline of Western Cape Province in South Africa. This area is 7 km east of George in an area characterized by the occurrence of the Table Mountain Group aquifer. The research presented in this thesis formed part of a Water Research Commission (WRC) project titled “The Impacts of Commercial Plantation Forests on Groundwater Recharge and Streamflow”. To achieve the aim of the current study, three objectives were formulated: i) to characterize the dominantly occurring recharge mechanism ii) to determine long-term groundwater recharge estimates, and iii) to assess the effect of plantation forests on groundwater recharge. As part of characterizing the dominant recharge mechanism in the area, a conceptual groundwater recharge model of the area was developed to explain the recharge mechanism and facilitate an improved understanding of recharge estimates. The model was based on a theoretical understanding and previous investigations conducted in the study area. Methods such as environmental stable isotopes and hydrochemistry were used to refine the conceptual model by identifying the source of recharge and the dominant recharge mechanism. The occurrence and density of lineaments were used as a proxy to delineate potential recharge zones in the area. Recharge was estimated using the Rainfall Infiltration Breakthrough (RIB) and the Chloride Mass Balance (CMB) methods. Additionally, the effect of plantation forests on recharge was assessed using the HYDRUS-2D numerical model. The recharge estimates derived from the RIB and CMB techniques were verified using the published maps by Vegter (1995).

Commercial granular and fibrous activated carbons have been studied for the removal of heavy metals from aqueous solutions. A wood based activated carbon (AUG WHK) and an activated carbon cloth (KoTHmex TC-66 C) based on polyacrylonitrile fibre as a precursor, were oxidised for different periods of time using nitric acid, ozone and electrochemical methods to introduce various acidic groups at the surface, thereby, enhancing metal binding capacity. Modified samples were subsequently studied for the specific removal of cadmium and mercury ions in solution and compared with the performance of a commercially available weak acid fibrous exchange material (Ecofil-Deco Ltd. K-4). Carbonaceous adsorbents were physically characterised by scanning electron microscopy, surface area and porosimetry (using N2 adsorption at 77K). There was a decrease in BET surface area betweenu ntreateda nd oxidised samples. Acid and electrochemically oxidised samples were completely stable although there was clear evidence of physical damage to ozone-oxidised carbons. Samples were also chemically characterised by pH titration, direct titration, X-ray photoelectron spectroscopy and elemental analysis. A significant increase in oxygen content was obtained after oxidation, which increased the total ion exchange capacity by a factor of approximately 3.3 compared to commercial as-received carbonaceous adsorbents. As the degree of oxidation increased, the point of zero charge was shifted to lower pH values, i. e. from 4.5 to 3.6. (Continues...).

Thesis--Auburn University, 2009. / Abstract. Vita. Includes bibliographical references (p. 38).