Browsing by Subject "Pharmaceuticals"
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Item Enzymes : the new water/wastewater treatment chemical(2011-05) Garcia, Hector A.; Lawler, Desmond F.; Kinney, Kerry A.; Kirisits, Mary J.; Malina, Joseph F.; Kitto, George B.Pharmaceuticals and personal care products (PPCPs) are detected routinely in raw and treated municipal wastewater. Conventional wastewater treatment processes are not effective in removing PPCP; therefore, treated wastewater discharges are one of the main entry points for PPCPs into the aquatic environment, and eventually into drinking water supplies. The use of laccase-catalyzed oxidation for removing low concentrations of PPCPs from municipal wastewater after primary treatment is investigated. Oxybenzone was selected as a representative PPCP. Like many other PPCPs, oxybenzone is not recognized directly by the laccase enzyme. Therefore, mediators were used to expand the oxidative range of laccase, and the efficacy of this laccase-mediator system in primary effluent was evaluated. Eight potential mediators were investigated. The greatest oxybenzone removal efficiencies were observed when 2,2’-azino-bis(3-ethylbenzthiazoline-6sulphonic acid) (ABTS), a synthetic mediator, and acetosyringone (ACE), a natural mediator, were present. An environmentally relevant concentration of oxybenzone (10 µg/L) in primary effluent was removed below the detection limit after two hours of treatment with ABTS, and 95% was removed after two hours of treatment with ACE. Several mediator/oxybenzone molar ratios were evaluated at two different initial oxybenzone concentrations. Higher mediator/oxybenzone molar ratios were required at the lower (environmentally relevant) oxybenzone concentrations, and ACE required higher molar ratios than ABTS to achieve comparable oxybenzone removal. The oxidation mechanisms and kinetics of the ACE mediator was evaluated. A better understanding of the mediator oxidation process would lead to a better design of the laccase-mediator system. An alternative laccase-mediator treatment configuration, which allows the enzyme and mediator to react prior to coming in contact with the target PPCP, was investigated. This treatment configuration shows promise for further development since it might reduce laccase and mediator requirements. Oxidation byproducts generated by the laccase-mediator system were characterized and compared to those generated during ozonation. Enzymatic treatment generated byproducts with higher mass to charge (m/z) ratios, likely due to oxidative coupling reactions. The results of this study suggest that, with further development, a laccase-mediator system has the potential to extend the treatment range of laccase to PPCPs not directly recognized by the enzyme, even in a primary effluent matrix.Item Essays on pharmaceuticals and health care expenditures(2009-06-02) Karaca, ZeynalThe U.S. pharmaceutical industry has been remarkably successful in developing new treatments for many of the leading causes of morbidity and mortality. These new treatments and their high prices lead government and private parties to increase spending and raise the issue of access. Price and cost increases have stimulated insurance costs, raising questions about the value of new technologies. A key way to address the increase in pharmaceutical prices is to investigate the impact of newer therapies on overall health expenditure. There is a conflict among researchers about the benefits and costs of newer and better drugs. Some researchers argue that newer and better drugs keep people out of hospitals and provide significant cost savings. Another group of researchers argue in their work that newer drugs do not really provide significant cost savings. This dissertation investigates the impacts of break-through drug classes on overall health care expenditures. Empirical evidence presented in this dissertation shows that drugs belonging to new drug classes provide significant advances in treatment of conditions compared to other drugs. The results indicate that all new drug classes except Fluoroquinolones provide substantial cost savings on overall health care expenditures. This dissertation also explores the relations between FDA Therapeutic Drug Classification and total health care expenditures. It offers a better methodology by incorporating both the quality and the age of the drugs to capture their effects on total health care expenditures. It studies the impacts of the quality and the age of the drugs on the diseases of following therapeutic classes: musculoskeletal system and connective tissue, skin and subcutaneous tissue, neoplasm, mental disorders, nervous system and sense organs, circulatory system, respiratory system, digestive system, genitourinary system. The nature of therapeutic conditions coupled with their duration lead us to conclude that for some therapeutic categories newer priority drugs are preferable, for others newer standard drugs are better. The results suggest that there is no general rule to state that newer priority drugs decrease health care expenditures.Item The information content of options data applied to the prediction of clinical trial results(2010-12) Yarger, Stephen A., 1974-; Lawson, Kenneth Allen, 1952-; Rascati, Karen; Strassels, Scott; Garlappi, Lorenzo; Leslie, RyanFDA decisions and late-stage clinical trial results regarding new pharmaceutical approvals can cause extreme moves in the share price of small biopharmaceutical companies. Throughout the clinical trial process, many potential investors are exposed to market-moving information before such information is made available to the investing public. An investor who wished to profit from advance knowledge about clinical trial results may use the publicly traded options markets in order to increase leverage and maximize profits. This research examined options data surrounding the public release of information pertaining to the efficacy of clinical trials and approval decisions made by the FDA. Events were identified for small pharmaceutical companies with fewer than three currently approved drugs in an attempt to isolate the effect of individual clinical trial and FDA-related events on the share price of the underlying company. Option data were analyzed using logistic regression models in an attempt to predict phase II and III clinical trial outcome results and FDA new drug approval decisions. Implied volatility, open interest, and option contract delta values were the primary independent variables used to predict positive or negative event outcomes. The dichotomized version of a predictor variable designed to estimate total investment exposure incorporating open interest, option contract delta values, and the underlying stock price was a significant predictor of negative pharmaceutical related events. However, none of ii the variables examined in this research were significant predictors of positive drug research related events. The estimated total investment exposure variable used in this research can be applied to the prediction of future clinical trial and FDA decision related events when this predictor variable shows a negative signal. Additional research would help confirm this finding by increasing the sample size of events that potentially follow the same pattern as those examined in this research.Item Kinetics of ciprofloxacin degradation by ozonation : effects of natural organic matter, the carbonate system, and pH(2010-08) Marron, Corin Ann; Katz, Lynn EllenThe presence of pharmacologically active and persistent compounds in drinking water sources is an environmental and public health concern. Sources of pharmaceuticals in the aquatic environment include wastewater treatment plant effluents and veterinary use. Antibiotics are of special concern because of their role in the spread of bacterial resistance. Conventional drinking water treatment processes are often ineffective for removing trace organic contaminants. Ozonation processes have demonstrated the ability to remove pharmaceutical compounds from drinking water supplies. During the ozonation of drinking water, the primary oxidants are ozone and hydroxyl radicals formed during the decomposition of ozone. Both oxidants contribute to the removal of pharmaceutical compounds; however, the relative rates of destruction by these two oxidants depends on the treatment operating conditions, the background water chemistry and the structure and reactivity of the target compound. This study investigated the relative impact of natural water characteristics, such as pH, the carbonate system, and natural organic matter, on the removal of the fluoroquinolone antibiotic ciprofloxacin by ozonation processes. Rate constants for k"O3, Cip obtained at pH 7 were approximately one order of magnitude higher than at pH 5 because ciprofloxacin changes from a positively charged cation to a neutral species over this pH range. The results showed that there was very little variation of the rate constants for ciprofloxacin oxidation by O₃ or hydroxyl radicals regardless of the carbonate concentration or the presence of the two organic matters studied in this research. Typical values for k"O3, Cip and k"HO°, Cip obtained at pH 7 ranged between 1.49x10⁴ and 1.64x10⁴ M⁻¹s⁻¹ and 1.29x10¹⁰ to 1.80x10¹⁰ M⁻¹s⁻¹, respectively. However, the presence of carbonate and other hydroxyl radical scavengers did have an impact on O₃ and hydroxyl radical exposure. The relative impact of these two oxidants changed depending on the pH of the system and the presence of carbonate and natural organic matter.Item Oxidation of pharmaceuticals : impacts of natural organic matter and elimination of residual pharmacological activity(2011-08) Blaney, Lee Michael; Lawler, Desmond F.; Katz, Lynn Ellen; Liljestrand, Howard M.; Richburg, John H.; Speitel Jr., Gerald E.; Kirisits, Mary JoAnthropogenically-derived substances, including pharmaceuticals and personal care products, endocrine-disrupting chemicals, and pesticides, are increasingly being detected in drinking water supplies and wastewater effluents. Concerns over the presence of these compounds in water supplies include their ability to impart toxicological activity, their capacity to spread antibiotic resistance, and their potential to affect cell-signaling processes. For these reasons, water treatment processes geared towards removal of these trace organic contaminants are vital. In this work, ozone was used to treat four pharmaceutical contaminants: ciprofloxacin, cyclophosphamide, erythromycin, and ifosfamide. Ciprofloxacin and erythromycin are antibiotic/antimicrobial compounds, and cyclophosphamide and ifosfamide are chemotherapy agents. Ozone effectively transformed all four pharmaceuticals, even in the presence of background natural organic matter, which exerts a considerable ozone demand. The apparent rate constants for the reaction of the pharmaceuticals with ozone at pH 7 were determined: 3.03 M-1s-1 for cyclophosphamide; 7.38 M-1s-1 for ifosfamide; 1.57×104 M-1s-1 for ciprofloxacin; and 7.18×104 M-1s-1 for erythromycin. Cyclophosphamide and ifosfamide, which do not react quickly with ozone, exhibited high rate constants (2.7×109 M-1s-1) for transformation by hydroxyl radicals, which are formed through ozone decomposition. Nevertheless, complete removal of cyclophosphamide and ifosfamide was achievable using a novel continuous aqueous ozone addition reactor and an ozone-based advanced oxidation process (peroxone). In ozone-based processes, pharmaceuticals are systematically transformed via complex oxidative pathways towards CO2, H2O, and the oxidized forms of other elements. Intermediate oxidation products containing oxygen atoms or hydroxyl groups substituted into the chemical structure of the parent pharmaceutical were identified using liquid chromatography-mass spectrometry (LC-MS). Given the structural similarity of intermediate oxidation products to the parent pharmaceuticals, an antimicrobial activity assay was employed to monitor the removal of pharmacological activity associated with ciprofloxacin, erythromycin, and their respective intermediate oxidation products throughout treatment. For solutions containing ciprofloxacin or erythromycin, ozone was able to completely eliminate the corresponding antimicrobial activity. Ciprofloxacin intermediate oxidation products were pharmacologically active; however, erythromycin’s intermediate products did not contribute to the residual antimicrobial activity. These results suggest that the design of conventional and advanced ozone-based processes must incorporate ozone demand from background organic matter and account for destruction of pharmacologically active intermediates.Item Ozonation of erythromycin and the effects of pH, carbonate and phosphate buffers, and initial ozone dose(2011-08) Huang, Ling, Ph. D.; Katz, Lynn Ellen; Lawler, Desmond F.The ubiquitous presence and chronic effect of pharmaceuticals is one of the emerging issues in environmental field. As a result of incomplete removal by sewage treatment plants, pharmaceuticals are released into the environment and drinking water sources. On the other hand, conventional drinking water treatment processes such as coagulation, filtration and sedimentation are reported to be ineffective at removing pharmaceuticals. Therefore, the potential presence of pharmaceuticals in finished drinking water poses a threat on public health. Antibiotics, as an important group of pharmaceuticals, are given special concerns because the potential development of bacteria-resistance. Ozonation and advanced oxidation processes are demonstrated to be quite effective at removing pharmaceuticals. The oxidation of pharmaceuticals is caused by ozone itself and hydroxyl radicals that are generated from ozone decomposition. Whether ozone or hydroxyl radicals are the primary oxidant depends on the specific pharmaceutical of interest and the background water matrix. In this research, erythromycin, a macrolide antibiotic, was chosen as the target compound because of its high detection frequency in the environment and its regulation status. The objective of this research was to investigate the removal performance of erythromycin by ozonation from the standpoint of kinetics. The effects of pH, carbonate and phosphate buffers, and initial ozone dose on ozonation of erythromycin were also studied. The second-order rate constant for the reaction between deprotonated erythromycin and ozone was determined to be 4.44x10⁹ M⁻¹·s⁻¹ while protonated erythromycin did not react with ozone. Ozone was determined to be the primary oxidant for erythromycin removal by ozonation. pH was found to have great positive impact on the degradation of erythromycin by ozonation due to the deprotonation of erythromycin at high pH. Carbonate and phosphate buffers were found to have negligible effects on the degradation of erythromycin by ozonation. Initial ozone dose showed a positive impact on the total erythromycin removal rate by ozonation.Item Pharmaceutical governance in Brazil : globalization, institutions and AIDS(2010-12) Flynn, Matthew Brian; Roberts, Bryan R., 1939-; Buckley, Cynthia J.; Ward, Peter; Ugalde, Antonio; Charrad, Mounira; Wilson, RobertThe Acquired Immune Deficiency Syndrome (AIDS) caused by the human immunodeficiency virus (HIV) represents one of the biggest challenges facing today's globalized world. Meanwhile, transnational drug companies have strengthened their market positions in developing countries as a result of the Agreement on Trade-Related Aspects of Intellectual Property (or TRIPS). Patent protection provided by TRIPS has led to higher prices and reduced access to essential medicines. Low- and middle-income countries are under increased pressure to provide expensive life-saving medicines to their citizens. Brazil's AIDS program is deemed successful in reducing morbidity and mortality rates through universal provision of free AIDS medicines. The program's sustainability came under threat as the result of TRIPS, pressures by transnational corporations, and trade threats by the US government. The research question that drove my dissertation centered on the impact of these threats on policy space available to Brazilian government to sustain its universal social program. How has the incorporation of patent protections for drugs affected the ability of local firms to develop pharmaceutical technology and challenged states like Brazil to fulfill social democratic obligations? Under what conditions can a developing country challenge the interests of transnational drug companies? I employed mixed methods for gathering and analyzing data. These included ethnographic field techniques, content analysis, and archival research. My findings are threefold. First, TRIPS has increased the power of foreign firms to secure monopoly positions in Brazil’s drug markets and weakened Brazil's labs to quickly make generic copies of essential medicines. Second, policy space, though curtailed due to external pressures and treaty obligations, expanded through the development of symbolic power, or what I call "reputational dividends," based on a successful social program. Third, by adroitly marketing its banner AIDS program by employing human rights principles, health officials constructed a triple alliance between the state, local private drug manufacturers, and domestic activists tied into transnational advocacy networks. I employ institutional and power analyses to examine the changing sources of power for transnational capital, social movements, and state actors, as well as analyze the impact patent protection has on the ability of Brazilian firms to produce medicines locally. I posit that globalization results in the formation of strong domestic coalitions who are capable of exploiting the "reputational dividends" of a successful social program in order to contest transnational corporate power. This symbolic form of power appears particularly well-disposed for "middle-income" countries that lack the material forms of power held by a global hegemon or transnational corporations.Item The Transannular bis-Michael Reaction in the Synthetic Studies of Celastrol and the Development of Novel Palladium-Catalyzed Reactions(2013-11-11) Kaiser, Thomas MaxwellPharmaceutical R&D is currently undergoing a productivity crisis. Also, the loss of activity of established medicines continues to reduce the pool of agents capable of treating infectious diseases. Small molecule synthesis and synthetic methodology development continue to be essential scientific endeavors due to the ability of synthetic chemistry to create new starting points for the development of medicines. Therefore, in order to increase the ability to discover new medicines, more efficient synthetic strategies and transformations capable of generating structurally complex drug-like molecules are required. This work explored the transannular bis-Michael reaction (TMR) as a potential method to access polycyclic natural products in an efficient manner. We sought to develop an expedient route to an all-carbon Z,E macrocyclic precursor to the TMR and we then evaluated whether the Z,E isomer would follow our proposed model for the TMR. Our strategy relied on a 1,3-dipolar cycloaddition to access the TMR precursor. However, this 1,3-dipolar synthetic route had a low synthetic efficiency. Consistent with our other studies, this Z,E-macrocyclic bis-enone was found to be inactive in the transannular bis-Michael reaction cascade for the conditions evaluated. En route, we also discovered that our 1,3-dipolar cycloaddition gave a rare 3,4-disubstituted isoxazole under kinetic reaction conditions. We also demonstrated that the dipolar cycloaddition is reversible and the thermodynamic 3,5-disubstituted isoxazole can be obtained through isomerization of its 3,4-disubstituted isomer under elevated temperature. Our initial mechanistic studies support the role of hydrogen-bonding in accelerating the isomerization process. Our work in developing new palladium-catalyzed reactions resulted in a novel palladium-catalyzed enamine Heck reaction. This reaction is capable of generating ?,?-unsaturated ketones directly from aldehydes and vinyl iodides. However, the limitations of scope in both vinyl iodide and aldehyde severely limit the synthetic utility of the reaction described herein. Also, our work clearly demonstrated a novel enantioconvergent approach to 3-allyl-3-alykl-indolenines through the use of a chiral palladium/trialkylborane dual catalyst system. We suggest a greater role of trialkyl borane beyond allylic alcohol activation in previous allylation examples employing R_(3)B/allyl alcohol as the allyl source. Finally, we extended or understanding of the role of Et_(3)B to the Tamaru allylation. The Lewis acid, Et3B, facilitates enolization and behaves as a co-catalyst to effect the allylation of aldehydes. We have also begun developing an enantioselective version of this reaction that suffers from low enantioselectivity. This reaction was shown to be selective for aldehydes as ketones did not react under the described conditions.Item Using science to innovate : explaining productivity in the pharmaceutical industry innovation activities(2012-08) Stone, Alexandra Bella; Dukerich, Janet M.; Stolp, Chandler; Wilson, Robert; Osborne, Cynthia; Callan, Benedicte; Henderson, AndrewScientific and technological (S&T) advances underpin opportunities for innovation in the pharmaceutical industry. Government-funded research institutions and firms perform biomedical research to generate S&T advances and enable pharmaceutical innovation. Previous research found that the number of new drugs approved by the US Food and Drug Administration (FDA) has stagnated. The observed stagnation has been interpreted as a decline in the return on research investments. The apparent decline in productivity may be due to the increasing technological difficulty of using S&T advances to develop new drugs and the organizational complexity of incorporating S&T advances generated by government-funded research institutions and firms to develop a new drug. I apply theories of organizational learning to examine how the use of S&T advances to develop new drugs affects the productivity of drug development activities, measured as the time taken to complete early stage pre-clinical research and late stage clinical development activities. I have constructed a novel data set that maps the production and utilization of S&T advances in three phases of market-oriented drug development. By measuring productivity at the project level, I am able to model productivity as the time taken to complete a R&D project as a function of three factors: (1) the technological characteristics of the drug; (2) the use of components generated by other entities; and (3) the research capabilities of the innovating firm. These models enable me to identify technological and organizational factors that affect the efficiency with which S&T advances are transformed into new drugs. Analyses indicate that different technological and organizational factors affect the productivity of pre-clinical research and clinical development. While the time taken to complete a pre-clinical research project is largely determined by the complexity and innovativeness of the drug, the time taken to complete clinical development is a function of the firm's R&D previous experience. The time taken to complete the entire drug development project is determined by the complexity of pre-clinical research and the firm's R&D capabilities. The results are discussed in detail along with policy implications.