Dissertations / Theses on the topic 'Drug selection'
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Grice, Christopher Martin. "Peptide aptamer selection for antifungal drug discovery and diagnostics." Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/51495.
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The demand for more effective fungal diagnostics and therapeutics is becoming increasingly urgent with increases in incidence of fungal diseases, antifungal resistance and lack of rapid diagnosis resulting in high mortality rates. The research described in this thesis evaluates the Aspergillus fumigatus pH-signalling receptor PalH (which non-redundantly regulates processing of the transcription factor PacC, and is essential for pathogenicity), as a viable therapeutic target. To assess intracellular modulation of PalH functionality, a novel proof-of-principle library of peptide aptamers (PAs), constrained within an inert thioredoxin A (TrxA) scaffold, was constructed for the expression and isolation of anti-PalH PAs using a S. cerevisiae membrane two-hybrid (YMTH) assay. Three PAs demonstrating significant binding to PalH were recovered. In parallel, peptide antigens representing the four PalH surface exposed regions, were synthesised to permit the generation of murine monoclonal antibodies (mAbs) to PalH. Both anti-PalH PAs and anti-PalH mAbs were found to modulate PalH functionality towards a gain-of-function alkaline-mimicking phenotype. These findings demonstrate that therapeutic modalities having the ability to modulate PalH functionality, are accessible by such means and availability of such reagents can assist further characterisation of PalH mode of action. To gain insight into a proposed role for PalH oligomersation in pH signalling and pathogenicity, co-immunoprecipitation of differentially tagged PalH variants derived from A. nidulans diploid analysis, confirmed constitutive presence of an oligomer regardless of environmental pH. Finally, the YMTH assay was further exploited to isolate novel interactors of PalH which could serve as alternative therapeutic targets. The proteins CipC (antibiotic response-like protein), COMPASS complex subunit Sdc1, and a hypothetical protein, were isolated as PalH-interacting moieties impacting pH-dependent activities in A. fumigatus.
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Olofsson, Sara K. "Relation Between Drug Exposure and Selection of Antibiotic Resistant Bacteria." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis Univ.-bibl. [distributör], 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7197.
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Eng, Jeffrey K. L. "Genetic selection by ivermectin on Onchocerca volvulus." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111844.
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Onchocerca volvulus is a parasitic filarial nematode responsible for human onchocerciasis, a disease commonly known as "River Blindness". Although there are no well documented cases of ivermectin resistance in O. volvulus, reports of suboptimal responses to ivermectin have appeared. The purpose of this thesis was to examine genetic polymorphisms in O. volvulus and to determine whether there was genetic evidence of ivermectin selection on O. volvulus genes. Analysis of 17 genes from O. volvulus was undertaken in two populations of worms, either from ivermectin-naive patients or from patients who had been repeatedly treated with ivermectin annually. In 14 of the genes no differences in genetic polymorphism were found (although polymorphisms were identified). However, chi square analysis (chi2=0.05) indicated significant differences in allele frequencies for a P-glycoprotein, a beta-tubulin and a putative dyf=8 gene. Analysis of the O. volvulusbeta-tubulin alleles identified three amino acid substitutions in the H3 region with ivermectin selection. Microtubules play a key structural role in the formation of neurons, and in ivermectin-resistant Haemonchus contortus, amphidial neurons show distorted microtubule bundles. Polymerization and depolymerization assays of the recombinant O. volvulus beta-tubulin alleles showed interesting differences between the polymerized tubulin using the two different alleles. It is speculated that similar differences could cause the disorganization of the microtubules identified in the amphidial neurons in ivermectin resistant H. contortus. In addition to the coding mutations, a 24 bp deletion in the adjacent intron to the H3 was detected. A PCR diagnostic assay was developed to genotype individual macro- and microfilariae. Further analyses were conducted to investigate the possibility of a direct relationship between ivermectin and beta-tubulin. Data obtained from equilibrium dialysis experiments indicated that BODIPY FL ivermectin bound to purified O. volvulus alpha- and beta-tubulins. More interesting, non-fluorescent ivermectin and taxol competed with the BODIPY FL ivermectin. The work presented in this thesis provides evidence of genetic selection by ivermectin on O. volvulus and suggests a putative binding site for ivermectin on tubulin. These data provide novel information on ivermectin selection in O. volvulus and on the possible involvement of tubulin in ivermectin resistance.
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Larsson, Sonny. "Mistletoes and Thionins : as Selection Models in Natural Products Drug Discovery." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7705.
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Nilsson, Annika. "Bacterial adaptation to novel selection pressures /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-192-X/.
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Kahatapitiya, Prathibha Chathurani. "Enrichment of skeletal muscle stem cell transplantation using chemotherapeutic drugs." Thesis, The University of Sydney, 2009. http://hdl.handle.net/2123/4050.
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The BCNU + O6benzylguanine (O6BG) driven selective enrichment strategy was first established for enhanced transplantation of hematopoietic stem cells. This study describes a novel application of this BCNU + O6BG driven selective enrichment strategy in skeletal muscle stem cell transplantation. Furthermore, this study addresses the three main limitations observed in previously reported skeletal muscle stem cell transplantation strategies. Limitation of ineffective donor cells which lack the ability for successful engraftment was overcome by using a heterogeneous population of donor cells which are present during a normal skeletal muscle regeneration response. The limitation of donor cell death upon transplantation as a result of competition from the endogenous stem cells of the host muscles was overcome by elimination of host muscle stem cells with BCNU + O6BG treatment. Efficiency of elimination of host muscle stem cells was further demonstrated by the complete inhibition of a regeneration response up to 3 months in injured, BCNU + O6BG treated muscles. The limitation of localised engraftment as a result of intramuscular injection of donor cells was also addressed. The transplanted donor cells demonstrated the ability to migrate via systemic circulation. This characteristic of the donor cells would allow the transplantation of cells via intraarterial or intravenous delivery which would overcome the limitation of localised engraftment. Finally, application of the BCNU + O6BG driven selective enrichment strategy in skeletal muscle stem cell transplantation demonstrated enhanced engraftment. This is the first reported attempt of enhanced stem cell transplantation in a solid tissue achieved upon application of the BCNU + O6BG driven selective enrichment strategy. This study provides the basis for application of the BCNU + O6BG driven selective enrichment strategy in other tissues where stem cell transplantation is considered.
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Kahatapitiya, Prathibha Chathurani. "Enrichment of skeletal muscle stem cell transplantation using chemotherapeutic drugs." University of Sydney, 2009. http://hdl.handle.net/2123/4050.
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Doctor of Philosophy (PhD)The BCNU + O6benzylguanine (O6BG) driven selective enrichment strategy was first established for enhanced transplantation of hematopoietic stem cells. This study describes a novel application of this BCNU + O6BG driven selective enrichment strategy in skeletal muscle stem cell transplantation. Furthermore, this study addresses the three main limitations observed in previously reported skeletal muscle stem cell transplantation strategies. Limitation of ineffective donor cells which lack the ability for successful engraftment was overcome by using a heterogeneous population of donor cells which are present during a normal skeletal muscle regeneration response. The limitation of donor cell death upon transplantation as a result of competition from the endogenous stem cells of the host muscles was overcome by elimination of host muscle stem cells with BCNU + O6BG treatment. Efficiency of elimination of host muscle stem cells was further demonstrated by the complete inhibition of a regeneration response up to 3 months in injured, BCNU + O6BG treated muscles. The limitation of localised engraftment as a result of intramuscular injection of donor cells was also addressed. The transplanted donor cells demonstrated the ability to migrate via systemic circulation. This characteristic of the donor cells would allow the transplantation of cells via intraarterial or intravenous delivery which would overcome the limitation of localised engraftment. Finally, application of the BCNU + O6BG driven selective enrichment strategy in skeletal muscle stem cell transplantation demonstrated enhanced engraftment. This is the first reported attempt of enhanced stem cell transplantation in a solid tissue achieved upon application of the BCNU + O6BG driven selective enrichment strategy. This study provides the basis for application of the BCNU + O6BG driven selective enrichment strategy in other tissues where stem cell transplantation is considered.
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Njoroge, Joyce Muthoni. "Ivermectin selection and characterization of the life history traits of Heligmosomoides polygyrus (Nematoda)." Thesis, McGill University, 1995. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=23417.
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A stock "parent" (S) strain of the mouse parasite Heligmosomoides polygyrus was exposed to increasing levels of ivermectin at the L4 stage for 15 generations. A Passage line was also developed from the parent strain parallel with the ivermectin selected line to control for the effects of rapid passage of the parasite from host to host during drug selection. A dose titration trial indicated 1.5 fold resistance had developed in the ivermectin selected strain at the 8th generation (IVM-8) both at the L4 and adult stage. A higher dose of drug was required to kill the L4 stage compared to the adults at generation 8. Additional selection pressure for 7 generations (IVM-15) did not change the resistance status of adult worms. The Passage strains (P-8 and P-15) remained susceptible to drug. The life history traits of the parent strain (S), the ivermectin selected (IVM-8 and IVM-15) and the Passage (P-8 and P-15) strains were then compared. Eight generations of selection with ivermectin (IVM-8) resulted in an increase in establishment 8 days post-infection (pi) but decreased egg output and worm burden over 4 months compared with strain S. However these effects were not seen after 15 generations of drug selection. The ivermectin selected strain (IVM-15) had similar establishment, egg production and worm burden as the parent strain (S). Establishment in strain P-8 was intermediate and not different from S or IVM-8 however 15 generations of passage (strain P-15) resulted in higher establishment and more rapid development to adult. This was also reflected in the net egg output and worm burden during the first month of infection. There were no differences in per capita fecundity among the five strains. Environmental pressure exerted by passage of H. polygyrus from host to host rather than ivermectin selection caused shifts in some life history traits of this nematode.
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Nalunkuma, Kazibwe Anne J. "Factors influencing the spread and selection of drug resistance in Human African Trypanosomiasis." Thesis, University of Glasgow, 2008. http://theses.gla.ac.uk/381/.
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A growing problem with drug resistance in Human African Trypanosomiasis has necessitated the implementation of screening programmes to monitor for its spread. This thesis describes the study of several factors that can influence the selection and propagation of drug resistance in T. brucei. Human African Trypanosomiasis (HAT) is caused by T. brucei gambiense and T. brucei rhodesiense. The few drugs used for the treatment of the disease are either toxic, cause severe side effects or suffer from parasite resistance. The T. brucei P2 transporter, which is encoded by the gene TbAT1, mediates uptake of melaminophenyl arsenicals and diamidines. Reduced P2 uptake is associated with drug resistance. A number of point mutations found in a laboratory derived melarsoprol resistant T. brucei stock (STIB 777R) allowed development of a PCR/RFLP based molecular method to identify resistance alleles. By 1999, 20-30% of patients treated in Omugo, NW Uganda were failing to respond to melarsoprol. PCR/RFLP analysis indicated that mutant alleles accounted for 58.5% of those in circulation. Melarsoprol was withdrawn in 2001 and by 2003 mutant TbAT1 alleles accounted for only 14% of those in circulation in NW Uganda. The current study aimed to determine the incidence of the PCR/Sfa NI TbAT1 mutant alleles in 2006, some five years after melarsoprol had been withdrawn as first-line treatment. Successful molecular analysis of 91 of 132 (68.9%) T. b. gambiense field isolates from Omugo and Moyo in NW Uganda indicated the presence of only TbAT1 wild type alleles. Mutant alleles thus appear to have disappeared. This may be the result of parasite fitness cost following the withdrawal of melarsoprol as a stage II first-line drug from Omugo health centre, Arua, since 2001. This apparent instability of TbAT1 mutants in the field may be exploited for rational or alternating use of melarsoprol and eflornithine (DFMO) to ensure a longer life for eflornithine, delaying the onset of resistance. Insight into the overall population structure of the T. b. gambiense from Omugo, Arua (N=54) and Moyo (N=17) was obtained using mini/microsatellite marker analysis. Genetic diversity was observed to be more intra than inter regional. Multilocus genotype data analysis revealed the Omugo, Arua, population was genetically distinct from the Moyo population (Nei’s genetic distance=0.176). The evidence indicated surprisingly little genetic exchange with an excess in homozygosity (Fis >0) and alleles in linkage disequilibrium (P<0.05) within the Omugo, trypanosome population. This excess in homozygosity may be due to population sub-structuring, trypanosome inbreeding, or migration of patients. The latter is likely occurring from the neighbouring T. b. gambiense endemic disease focus in Southern Sudan. The findings suggested that the T. b. gambiense from Arua is not panmictic, clonal or epidemic but there is some level of genetic exchange. The possibility that T. b. gambiense can infect animals raises the prospect that wild or domestic animals may act as a reservoir and that a veterinary link to gambiense Human African Trypanosomiasis exists. Treatment of animals for babesiosis and trypanosomes with diminazene, uptake of which is mediated through TbAT1/P2 could select for P2-defective drug resistant trypanosomes, thereby threatening control of the human disease as well. Species detection by PCR for animal and human trypanosomes in dog isolates (N=190) from the tsetse fly endemic Jos Plataeu, Nigeria did not reveal T. b. gambiense, but multiple infections with T. brucei (95%), T. vivax (89%), and subspecies T. congolense forest (54%) and savannah (50%) were detected. The dogs were also infected with other parasites, including Babesia canis (22%) and Hepatozoon canis (16%). Multiple infections can make correct diagnosis difficult and the infections are likely to be missed by the less sensitive microscopy method. The trypanocidal action of the diamidine group of trypanocides, diminazene, pentamidine and furamidine (DB75) are principally mediated through the TbAT1/P2. In addition, pentamidine is taken up by two additional T. brucei transporters called High Affinity Pentamidine Transporter (HAPT1) and the Low Affinity Pentamidine Transporter (LAPT1). DB75 also has a secondary unknown route. Loss of TbAT1/P2 leads to significant resistance to DB75 and diminazene but not pentamidine. Identification of other markers of resistance is necessary to determine if other routes of drug entry do exist apart from P2 and whether these can be exploited for the delivery of new trypanocides into the trypanosomes. Adaptation of the T. brucei tbat1 knock-out cell line to higher concentrations of diminazene by in vitro selection for resistance led to loss of HAPT1. The resultant phenotype was similar to the previously characterised pentamidine resistant clone B48, but more resistant to diminazene and DB75. The adapted line was still capable of accumulating 1 µM radiolabelled diminazene suggesting both HAPT1 and LAPT1 as possible routes for diminazene uptake. Adaptation of the T. brucei tbat1 knock-out cell line to a high concentration of DB75 over the same 6 months period did not lead to increased resistance. Overall the project has confirmed an important role for tbat1/P2 in development of resistance to melarsoprol in the field. Importantly, it appears that removal of the selection pressure of melarsoprol leads to a loss of tbat1 alleles associated with resistance in a population of trypanosomes capable of genetic exchange in NW Uganda. Although evidence for a dog reservoir for T. b. gambiense in Nigeria was lacking in this study, a risk of selecting resistance in animals must remain high on any list of consideration. I have further shown that the diamidine drug, diminazene, used in veterinary medicine also appears to enter T. brucei via the HAPT1 transporter, as well as the P2 transporter. Loss of HAPT1 through selection with diminazene leads to high level pentamidine resistance, which could indicate a further risk in selection of human infectious trypanosomes also resistant to drugs like pentamidine.
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Pulido, Gomez Amalia. "Drug-Related Violence and Party Behavior: The Case of Candidate Selection in Mexico." Thesis, University of North Texas, 2018. https://digital.library.unt.edu/ark:/67531/metadc1248489/.
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This dissertation examines how parties respond and adapt their behavior to political violence. Building a theoretical argument about strategic party behavior and party capture, I address the following questions: How do parties select and recruit their candidates in regions with high levels of violence and the pervasive presence of VNAs? Do parties respond to violence by selecting certain types of candidates who are more capable of fighting these organizations? Do parties react differently at different levels of government? And finally, how do VNSAs capture political selection across at different levels of government? I argue that in regions where there is high "uncertainty," candidate selection becomes highly important for both party leaders and DTOs. Second, I argue that as violence increases and the number of DTOs also, criminal organizations, as risk-averse actors, will capture candidate selection. I posit that as violence increases, there is a greater likelihood that candidates will have criminal connections. To test my theory, I use the case of Mexico. Violence in Mexico and the presence of criminal organizations across the country has experienced a great deal of variation since the 1990s. In Chapter 2, I find that violence affects the gubernatorial candidate selection of the PRI, PAN and PRD. In high violence states, parties select gubernatorial candidates with long experience in subnational politics compared to other types of experiences. In chapter 3, however, I find that at the municipal level not all the parties respond equally to violence. As a municipality becomes more violent, the PRI and PAN party leaders are more likely to select mayoral candidates who were either state or federal deputies or candidates who were both. In contrast, the PRD is likely to recruit state deputies as a function of violence, but not national deputies or candidates who were deputies at both the state and federal level. Interestingly, I find that as the municipality becomes more violent, party leaders are less likely to recruit inexperienced candidates. This result suggests that parties do indeed respond to levels of violence. Finally, in Chapter 5, I show that criminal organizations capture candidate selection to reduce uncertainty. As utility-maximizing actors, DTOs seek to influence the selection of candidates as a function of violence. At the state level, criminal organizations are more likely to capture candidate selection in states with the presence of multiple DTOs. Party capture is more likely to happen in states where more than one DTO are fighting to control the turf. I show that criminal organizations at the state level equally capture all parties. This finding reveals that DTOs are diversifying their political connections. While under the dominant party regime, they colluded with PRI officials, under the new political Mexican democratic configuration, DTOs are establishing other political relationships with different political parties.
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Wang, Guanhua 1970. "Genetic variation in P-glycoprotein in Haemonchus contortus following ivermectin selection." Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=79203.
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Resistance to ivermectin (IVM) in Haemonchus contortus has developed in many countries and its mechanism is still under investigation. P-glycoproteins (P-gp) are transmembrane proteins that can transport drugs out of cells. Researchers have found that there is polymorphism in a P-gp gene from H. contortus between IVM-selected and unselected worms. Three main P-gp polymorphs were identified, polymorph A was found to be related to IVM selection, while polymorphs B and X were associated with susceptibility. The purpose of this research is to investigate the genetic variations in P-glycoprotein that are associated with IVM selection or susceptibility in H. contortus. Total RNA and genomic DNA were extracted from individual male adult worms of IVM-selected and unselected strains of H. contortus. A fragment of the P-gp gene was amplified from the genomic DNA of individual worms and RFLP analysis was performed on the PCR product to genotype the corresponding worms. The homozygous worms that possessed polymorph A, B or X were identified.
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Jones, Derek. "Scalable Feature Selection and Extraction with Applications in Kinase Polypharmacology." UKnowledge, 2018. https://uknowledge.uky.edu/cs_etds/65.
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In order to reduce the time associated with and the costs of drug discovery, machine learning is being used to automate much of the work in this process. However the size and complex nature of molecular data makes the application of machine learning especially challenging. Much work must go into the process of engineering features that are then used to train machine learning models, costing considerable amounts of time and requiring the knowledge of domain experts to be most effective. The purpose of this work is to demonstrate data driven approaches to perform the feature selection and extraction steps in order to decrease the amount of expert knowledge required to model interactions between proteins and drug molecules.
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Lochmatter, Priska. "Cytokine selection and CD69 up-regulation in the diagnosis of delayed-type drug hypersensitivity." Bern : [s.n.], 2009. http://www.zb.unibe.ch/download/eldiss/09lochmatter_p.pdf.
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Al-Abbadi, Ibrahim. "Safe, therapeutic and economic pharmaceutical selection (STEPS) as a tool for drug formulary inclusion." Thesis, Queen's University Belfast, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.431400.
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Pugach, Pavel. "The evolutionary response of the HIV-1 ENV complex to selection pressures in vitro /." Access full-text from WCMC:, 2007. http://proquest.umi.com/pqdweb?did=1428842531&sid=4&Fmt=2&clientId=8424&RQT=309&VName=PQD.
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Reynolds, Alan. "Applied evolution : an integrated approach to studying life history traits in response to drug selection." Thesis, University of Glasgow, 2016. http://theses.gla.ac.uk/7673/.
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The use of chemical control measures to reduce the impact of parasite and pest species has frequently resulted in the development of resistance. Thus, resistance management has become a key concern in human and veterinary medicine, and in agricultural production. Although it is known that factors such as gene flow between susceptible and resistant populations, drug type, application methods, and costs of resistance can affect the rate of resistance evolution, less is known about the impacts of density-dependent eco-evolutionary processes that could be altered by drug-induced mortality. The overall aim of this thesis was to take an experimental evolution approach to assess how life history traits respond to drug selection, using a free-living dioecious worm (Caenorhabditis remanei) as a model. In Chapter 2, I defined the relationship between C. remanei survival and Ivermectin dose over a range of concentrations, in order to control the intensity of selection used in the selection experiment described in Chapter 4. The dose-response data were also used to appraise curve-fitting methods, using Akaike Information Criterion (AIC) model selection to compare a series of nonlinear models. The type of model fitted to the dose response data had a significant effect on the estimates of LD50 and LD99, suggesting that failure to fit an appropriate model could give misleading estimates of resistance status. In addition, simulated data were used to establish that a potential cost of resistance could be predicted by comparing survival at the upper asymptote of dose-response curves for resistant and susceptible populations, even when differences were as low as 4%. This approach to dose-response modeling ensures that the maximum amount of useful information relating to resistance is gathered in one study. In Chapter 3, I asked how simulations could be used to inform important design choices used in selection experiments. Specifically, I focused on the effects of both within- and between-line variation on estimated power, when detecting small, medium and large effect sizes. Using mixed-effect models on simulated data, I demonstrated that commonly used designs with realistic levels of variation could be underpowered for substantial effect sizes. Thus, use of simulation-based power analysis provides an effective way to avoid under or overpowering a study designs incorporating variation due to random effects. In Chapter 4, I 3 investigated how Ivermectin dosage and changes in population density affect the rate of resistance evolution. I exposed replicate lines of C. remanei to two doses of Ivermectin (high and low) to assess relative survival of lines selected in drug-treated environments compared to untreated controls over 10 generations. Additionally, I maintained lines where mortality was imposed randomly to control for differences in density between drug treatments and to distinguish between the evolutionary consequences of drug treatment versus ecological processes affected by changes in density-dependent feedback. Intriguingly, both drug-selected and random-mortality lines showed an increase in survivorship when challenged with Ivermectin; the magnitude of this increase varied with the intensity of selection and life-history stage. The results suggest that interactions between density-dependent processes and life history may mediate evolved changes in susceptibility to control measures, which could result in misleading conclusions about the evolution of heritable resistance following drug treatment. In Chapter 5, I investigated whether the apparent changes in drug susceptibility found in Chapter 4 were related to evolved changes in life-history of C. remanei populations after selection in drug-treated and random-mortality environments. Rapid passage of lines in the drug-free environment had no effect on the measured life-history traits. In the drug-free environment, adult size and fecundity of drug-selected lines increased compared to the controls but drug selection did not affect lifespan. In the treated environment, drug-selected lines showed increased lifespan and fecundity relative to controls. Adult size of randomly culled lines responded in a similar way to drug-selected lines in the drug-free environment, but no change in fecundity or lifespan was observed in either environment. The results suggest that life histories of nematodes can respond to selection as a result of the application of control measures. Failure to take these responses into account when applying control measures could result in adverse outcomes, such as larger and more fecund parasites, as well as over-estimation of the development of genetically controlled resistance. In conclusion, my thesis shows that there may be a complex relationship between drug selection, density-dependent regulatory processes and life history of populations challenged with control measures. This relationship could have implications for how resistance is monitored and managed if life histories of parasitic species show such eco-evolutionary responses to drug application.
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Ragan, Daniel T. "The role of selection effects in the drug-crime relationship a propensity score matching approach /." Tallahassee, Florida : Florida State University, 2009. http://etd.lib.fsu.edu/theses/available/etd-07152009-035659.
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Thesis (M.S.)--Florida State University, 2009.Advisor: Kevin M. Beaver, Florida State University, College of Criminology and Criminal Justice. Title and description from dissertation home page (viewed on Nov. 5, 2009). Document formatted into pages; contains ix, 85 pages. Includes bibliographical references.
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Vaidhyanathan, Shruthi. "Selection and Internalization Mechanisms of Targeting Ligands for Invasive Breast Cancer." University of Cincinnati / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1282570605.
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Gallant, Joseph P. "Natural selection and genetic variation in a promising Chagas disease drug target: Trypanosoma cruzi trans-sialidase." ScholarWorks @ UVM, 2017. http://scholarworks.uvm.edu/graddis/807.
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Rational drug design is a powerful method in which new and innovative therapeutics can be designed based on knowledge of the biological target aiming to provide more efficacious and responsible therapeutics. Understanding aspects of the targeted biological agent is important to optimize drug design and preemptively design to slow or avoid drug resistance. Chagas disease, an endemic disease for South and Central America and Mexico is caused by Trypanosoma cruzi, a protozoan parasite known to consist of six separate genetic clusters or DTUs (discrete typing units). Chagas disease therapeutics are problematic and a call for new therapeutics is widespread. Many researchers are working to use rational drug design for developing Chagas drugs and one potential target that receives a lot of attention is the T. cruzi trans-sialidase protein. Trans-sialidase is a nuclear gene that has been shown to be associated with virulence. In T. cruzi, trans-sialidase (TcTS) codes for a protein that catalyzes the transfer of sialic acid from a mammalian host coating the parasitic surface membrane to avoid immuno-detection. Variance in disease pathology depends somewhat on T. cruzi DTU, as well, there is considerable genetic variation within DTUs. However, the role of TcTS in pathology variance among and within DTU’s is not well understood despite numerous studies of TcTS. These previous studies include determining the crystalline structure of TcTS as well as the TS protein structure in other trypanosomes where the enzyme is often inactive. However, no study has examined the role of natural selection in genetic variation in TcTS. In order to understand the role of natural selection in TcTS DNA sequence and protein variation, we sequenced 540 bp of the TcTS gene from 48 insect vectors. Because all 48 sequences had multiple polymorphic bases, we examined cloned sequences from two of the insect vectors. The data are analyzed to understand the role of natural selection in shaping genetic variation in TcTS and interpreted in light of the possible role of TcTS as a drug target.
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Feole, Meghan. "Do Safety-related Fields Change Organizational Attractiveness and Job Pursuit Intentions When Drug-testing for Selection?" Thesis, Southern Illinois University at Edwardsville, 2018. http://pqdtopen.proquest.com/#viewpdf?dispub=10685553.
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Drug-testing for employment is still a controversial topic decades after being widely implemented by organizations as experts on both sides of the debate cite ethical and legal concerns among others. The public’s attitudes toward drug-testing, specifically Organizational Attractiveness (OA) and Job Pursuit Intentions (JPI), have predominantly been negative, although when there is a safety element to the job the view towards drug screening is more positive. The aim of this study was to examine if attitudes changed if safety-related jobs were involved. The participants were 106 students at a Midwestern university. Participants took either a pencil and paper or an online version of the survey, both which included job ads and follow up questionnaires testing OA, JPI, and attitudes toward drug-use. A 2x2 MANOVA found that participants had more OA toward organizations that did not drug-test for employment that toward those that did. Other hypotheses were not supported. Opportunities for additional research and possible limitations of the study are discussed.
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Zhang, Yi. "Application of Hyper-geometric Hypothesis-based Quantication and Markov Blanket Feature Selection Methods to Generate Signals for Adverse Drug Reaction Detection." University of Cincinnati / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1353343669.
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McGregor, Lynn Marie. "Methods for the Identification of Ligand-Target Pairs from Combined Libraries of Targes and Ligands." Thesis, Harvard University, 2014. http://dissertations.umi.com/gsas.harvard:11370.
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Advances in genome and proteome research have led to a dramatic increase in the number of macromolecular targets of interest to the life sciences. A solution-phase method to simultaneously reveal all ligand-target binding pairs from a single solution containing libraries of ligands and targets could significantly increase the efficiency and effectiveness of target-oriented screening efforts. Here, we describe interaction-dependent PCR (IDPCR), a solution-phase method to identify binding partners from combined libraries of small-molecule ligands and targets in a single experiment. Binding between DNA-linked targets and DNA-linked ligands induces formation of an extendable duplex. Extension links codes identifying the ligand and target into one selectively amplifiable DNA molecule. In a model selection, IDPCR resulted in the enrichment of DNA encoding all five known protein-ligand pairs out of 67,599 possible sequences.
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Vradi, Eleni [Verfasser], Werner [Akademischer Betreuer] Brannath, Richardus [Gutachter] Vonk, and Iris [Gutachter] Pigeot. "Biomarker selection and cutoff estimation in drug development / Eleni Vradi ; Gutachter: Richardus Vonk, Iris Pigeot ; Betreuer: Werner Brannath." Bremen : Staats- und Universitätsbibliothek Bremen, 2019. http://d-nb.info/1192909712/34.
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Bendall, Matthew Lewis. "Evaluating the Performance of Computational Approaches for Identifying Critical Sites in Protein-coding DNA Sequences." BYU ScholarsArchive, 2012. https://scholarsarchive.byu.edu/etd/3645.
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The ability to link a particular phenotype to its causative genotype is one of the most challenging objectives for biological research. Although the genetic code provides an explicit formula for determining the sequence of amino acid phenotypes produced by a given nucleotide sequence, identifying specific residues that are functionally important remains problematic. Many computational approaches have been developed that use patterns observed in DNA sequences to identify these critical sites. However, very few research studies have used empirical data to test whether these approaches are truly able to identify sites of interest.In most empirical studies, the actual protein function and selective pressures are unknown; thus it is difficult to assess whether computational approaches are correctly identifying critical sites. Here I present two studies that utilize well-characterized empirical systems to evaluate and compare the performance of several computational approaches. In both cases, the proteins under study have specific amino acid substitutions that are confirmed to alter protein function and expected to be constrained by natural selection. In chapter 2, I examine functional variants in angiopoietin-like protein 4 (ANGPTL4), a protein involved in regulating plasma triglyceride levels; loss-of-function variants in this gene are believed to decrease the risk of cardiovascular disease. I apply several computational approaches to identify functional variants, including phylogenetic approaches for detecting positive selection. In chapter 3, I investigate the emergence of drug-resistance in HIV-1 during the course of antiretroviral drug therapy. I compare the performance of eight selection detection methods in identifying drug-resistant mutations in 109 intrapatient datasets with HIV-1 sequences isolated at multiple timepoints throughout drug treatment.It is critical that we develop methods to detect positively selected sites. The ability to detect these sites in silico, without the need for expensive and time consuming assays, would be invaluable to researchers in evolutionary biology, human genetics, and medicine. Through the research presented in this thesis, I hope to provide insight into the strengths and weaknesses of current approaches, thereby facilitating future research towards the development and improvement of evolutionary models.
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Pokomi, Rostand Fankam. "Selection, synthesis and evaluation of novel drug-like compounds from a library of virtual compounds designed from natural products with antiplasmodial activities." University of the Western Cape, 2020. http://hdl.handle.net/11394/7950.
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Magister Pharmaceuticae - MPharmMalaria is an infectious disease which continues to kill more than one million people every year and the African continent accounts for most of the malaria death worldwide. New classes of medicine to combat malaria are urgently needed due to the surge in resistance of the Plasmodium falciparum (the parasite that causes malaria in humans) to existing antimalarial drugs. One approach to circumvent the problem of P. falciparum resistance to antimalarial drugs could be the discovery of novel compounds with unique scaffolds and possibly new mechanisms of action. Natural products (NP) provide a wide diversity of compounds with unique scaffolds, as such, a library of virtual compounds (VC) designed from natural products with antiplasmodial activities (NAA) can be a worthy starting point.
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Azizi, Bahareh. "Chemical Complementation: A Genetic Selection System in Yeast for Drug Discovery, Protein Engineering, and for Deciphering and Assembling Biosynthetic Pathways." Diss., Available online, Georgia Institute of Technology, 2005, 2005. http://etd.gatech.edu/theses/available/etd-07182005-102856/.
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Thesis (Ph. D.)--Chemistry and Biochemistry, Georgia Institute of Technology, 2006.Allen M. Orville, Committee Member ; Sheldon W. May, Committee Member ; Jung H. Choi, Committee Member ; Mostafa A. El-Sayed, Committee Member ; Donald F. Doyle, Committee Chair.
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Park, Daniel John. "Evolutionary Adaptation and Antimalarial Resistance in Plasmodium falciparum." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:11088.
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The malaria parasite, Plasmodium falciparum, has a demonstrated history of adaptation to antimalarials and host immune pressure. This ability unraveled global eradication programs fifty years ago and seriously threatens renewed efforts today. Despite the magnitude of the global health problem, little is known about the genetic mechanisms by which the parasite evades control efforts. Population genomic methods provide a new way to identify the mutations and genes responsible for drug resistance and other clinically important traits.
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Ward, Robert Dean. "The role of selection bias in estimates of the deterrence effect of drug testing : evidence from the national longitudinal survey of youth." Thesis, Monterey, Calif. : Springfield, Va. : Naval Postgraduate School ; Available from National Technical Information Service, 1999. http://handle.dtic.mil/100.2/ADA361980.
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Thesis (M.S. in Management) Naval Postgraduate School, March 1999."March 1999". Thesis advisor(s): Stephen L. Mehay, Rosalie L. Pacula. Includes bibliographical references (p. 81-82). Also available online.
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Buatois, Simon. "Novel pharmacometric methods to improve clinical drug development in progressive diseases." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCC133.
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Suite aux progrès techniques et méthodologiques dans le secteur de la modélisation, l’apport de ces approches est désormais reconnu par l’ensemble des acteurs de la recherche clinique et pourrait avoir un rôle clé dans la recherche sur les maladies progressives. Parmi celles-ci les études pharmacométriques (PMX) sont rarement utilisées pour répondre aux hypothèses posées dans le cadre d’études dites de confirmation. Parmi les raisons évoquées, les analyses PMX traditionnelles ignorent l'incertitude associée à la structure du modèle lors de la génération d'inférence statistique. Or, ignorer l’étape de sélection du modèle peut aboutir à des intervalles de confiance trop optimistes et à une inflation de l’erreur de type I. Pour y remédier, nous avons étudié l’apport d’approches PMX innovantes dans les études de choix de dose. Le « model averaging » couplée à un test du rapport de « vraisemblance combiné » a montré des résultats prometteurs et tend à promouvoir l’utilisation de la PMX dans les études de choix de dose. Pour les études dites d’apprentissage, les approches de modélisation sont utilisées pour accroitre les connaissances associées aux médicaments, aux mécanismes et aux maladies. Dans cette thèse, les mérites de l’analyse PMX ont été évalués dans le cadre de la maladie de Parkinson. En combinant la théorie des réponses aux items à un modèle longitudinal, l’analyse PMX a permis de caractériser adéquatement la progression de la maladie tout en tenant compte de la nature composite du biomarqueur. Pour conclure, cette thèse propose des méthodes d’analyses PMX innovantes pour faciliter le développement des médicaments et/ou les décisions des autorités réglementairesIn the mid-1990, model-based approaches were mainly used as supporting tools for drug development. Restricted to the “rescue mode” in situations of drug development failure, the impact of model-based approaches was relatively limited. Nowadays, the merits of these approaches are widely recognised by stakeholders in healthcare and have a crucial role in drug development for progressive diseases. Despite their numerous advantages, model-based approaches present important drawbacks limiting their use in confirmatory trials. Traditional pharmacometric (PMX) analyses relies on model selection, and consequently ignores model structure uncertainty when generating statistical inference. The problem of model selection is potentially leading to over-optimistic confidence intervals and resulting in a type I error inflation. Two projects of this thesis aimed at investigating the value of innovative PMX approaches to address part of these shortcomings in a hypothetical dose-finding study for a progressive disorder. The model averaging approach coupled to a combined likelihood ratio test showed promising results and represents an additional step towards the use of PMX for primary analysis in dose-finding studies. In the learning phase, PMX is a key discipline with applications at every stage of drug development to gain insight into drug, mechanism and disease characteristics with the ultimate goal to aid efficient drug development. In this thesis, the merits of PMX analysis were evaluated, in the context of Parkinson’s disease. An item-response theory longitudinal model was successfully developed to precisely describe the disease progression of Parkinson’s disease patients while acknowledging the composite nature of a patient-reported outcome. To conclude, this thesis enhances the use of PMX to aid efficient drug development and/or regulatory decisions in drug development
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Dudley, Dawn M. "HIV-1 Env impacting HIV-1 fitness, entry inhibitor drug sensitivity, and in vivo selection of a resistant virus to the microbicide PSC-Rantes /." Connect to text online, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1186757280.
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Thesis (Ph. D.)--Case Western Reserve University, 2007.[School of Medicine] Department of Molecular Biology and Microbiology. Includes bibliographical references. Available online via OhioLINK's ETD Center.
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Dudley, Dawn M. "HIV-1 ENV: IMPACTING HIV-1 FITNESS, ENTRY INHIBITOR DRUG SENSITIVITY, AND IN VIVO SELECTION OF A RESISTANT VIRUS TO THE MICROBICIDE PSC-RANTES." Case Western Reserve University School of Graduate Studies / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=case1186757280.
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Abdouslam, Nouradin Ali. "Impact of pollution on the dissemination of bacterial genes encoding resistance to quaternary ammonium compounds (QACs) and evidence for co-selection of drug resistance genes in environmental bacteria." Thesis, University of Warwick, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.437691.
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Oliveira, Fernando Araújo Rodrigues de. "Estratégias de apoio à captação de estudos clínicos patrocinados." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2018. http://hdl.handle.net/10183/181270.
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Os ensaios clínicos ocorrem cada vez mais em uma escala global e as pesquisas patrocinadas vem mudando para as regiões emergentes. A condução desses estudos traz benefícios para centros de pesquisa, pacientes e para o país como um todo. No entanto, a alocação de ensaios clínicos por companhias farmacêuticas multinacionais é um processo complexo determinado por múltiplos fatores e o conhecimento de quais fatores as companhias farmacêuticas valorizam mais ao alocar ensaios clínicos é escasso. Assim, compreender melhor esse processo é essencial para governos e centros de pesquisa que desejam atrair mais ensaios clínicos patrocinados por companhias farmacêuticas multinacionais. O objetivo deste trabalho é apresentar os atributos de centros de pesquisa clínica necessários para melhorar a captação de estudos clínicos patrocinados. Para identificar os fatores considerados determinantes da seleção de centros de pesquisa por patrocinadores e organizações representativas de pesquisa clínica foi desenvolvido um estudo descritivo-exploratório por meio da revisão da literatura através de buscas em bases de dados. As buscas resultaram na seleção de 16 materiais bibliográficos que abordaram a questão seleção de centros de pesquisa. Os fatores considerados mais críticos para a seleção foram disponibilidade de população alvo e capacidade de recrutamento, tempo de start-up e interesse e motivação da equipe do centro. Além disso, a infraestrutura é considerada um pré-requisito que pode inviabilizar a seleção e a qualidade de dados também é muito valorizada. Os custos diretos de execução do ensaio não foram considerados muito importantes, ao contrário dos custos indiretos. A partir do conhecimento dos pré-requisitos e dos fatores determinantes da seleção de um centro para um ensaio clínico multicêntrico patrocinado por companhias farmacêuticas, a Empresa Brasileira de Serviços Hospitalares poderá promover e direcionar os esforços para organizar uma rede de centros de pesquisa que pode ser muito atrativa.Clinical trials are increasingly occurring on a global scale and sponsored research has been shifting to emerging regions. Conducting these studies brings benefits to research centers, patients, and the country as a whole. However, the allocation of clinical trials by multinational pharmaceutical companies is a complex process determined by multiple factors and the knowledge of what factors pharmaceutical companies value most when allocating clinical trials is scarce. So, better understanding this process is essential for governments and research centers wishing to attract more clinical trials sponsored by multinational pharmaceutical companies. The objective of this work is to present the attributes of clinical research centers necessary to improve the capture of sponsored clinical studies. To identify the factors considered as determinants of the selection of research centers by sponsors and clinical research organizations, a descriptive-exploratory study was developed through the review of the literature through searches in databases. The search resulted in the selection of 16 bibliographic materials that addressed the issue of selection of research centers. The factors considered most critical for center selection were target population availability and recruiting capacity, start-up time, and interest and motivation of the center staff. In addition, infrastructure is considered a prerequisite that can make selection unfeasible and data quality is also highly valued. The direct costs of running the trial were not considered very important, as opposed to indirect costs. From the knowledge of the prerequisites and determinants of the selection of a center for a multi-center clinical trial sponsored by pharmaceutical companies, the Empresa Brasileira de Serviços Hospitalares can promote and direct efforts to organize a network of research centers that can be very attractive.
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Zhu, Jinfei. "Alcohol and illicit substance use in the food service industry assessing self-selection and job-related risk factors /." Columbus, Ohio : Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1221974238.
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Alayadhi, Nadyah Y. A. H. "Establishing an essential medicine list for the State of Kuwait." Thesis, University of Bradford, 2017. http://hdl.handle.net/10454/15742.
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The Health Sector at the state of Kuwait is facing many challenges. One of which is public expectations in health are high, and thus, the Ministry of Health (MOH) in Kuwait has amplified the health expenditure by 86% since 2007. And since the medicine budget represents half of the total MOH budget, it is proposed that the development in health policy might be a suitable tool to control the inflation within the health budget. This thesis examines the opportunities and challenges of introducing an EML in Kuwait and the factors influencing its effectiveness. A mixed-methodology approach has been used to enhance and validate the data, in the form of interviews, comparative studies and questionnaires. One major limitation to the research was the lack of previous data relating to this work, and the information should be gathered in person in the form of hard copies, and later, the data was analysed using qualitative and quantitative approaches. It has been attained that, the EML might be a valuable tool if adopted and implemented appropriately, EML adjustment to country health situation is crucial for successful utilisation and fulfilling the concept objectives. Standard Treatment Guidelines are fundamental part of EM selection process, in Kuwait there were lack in the uniformity of the local STG, but fortunately, there is an eagerness to innovate, and the medicine situation might benefit from a type of organisation, overall, if the EML implemented efficiently in Kuwait, it might help in improving the general health and control the inflation in MOH budget.
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Kierczak, Marcin. "From Physicochemical Features to Interdependency Networks : A Monte Carlo Approach to Modeling HIV-1 Resistome and Post-translational Modifications." Doctoral thesis, Uppsala universitet, Centrum för bioinformatik, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-109873.
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The availability of new technologies supplied life scientists with large amounts of experimental data. The data sets are large not only in terms of the number of observations, but also in terms of the number of recorded features. One of the aims of modeling is to explain a given phenomenon in possibly the simplest way, hence the need for selection of suitable features. We extended a Monte Carlo-based approach to selecting statistically significant features with discovery of feature interdependencies and used it in modeling sequence-function relationships in proteins. Our approach led to compact and easy-to-interpret predictive models. First, we represented protein sequences in terms of their physicochemical properties. This was followed by our feature selection and discovery of feature interdependencies. Finally, predictive models based on e.g., decision trees or rough sets were constructed. We applied the method to model two important biological problems: 1) HIV-1 resistance to reverse transcriptase-targeted drugs and 2) post-translational modifications of proteins. In the case of HIV resistance, we were not only able to predict whether the mutated protein is resistant to a drug or not, but we also suggested some new, previously neglected, mutations that possibly contribute to drug resistance. For all these mutations we proposed probable molecular mechanisms of action using literature and 3D structure studies. In the case of predicting PTMs, we built high accuracy models of modifications. In comparison to other methods, we were able to resolve whether the closest neighborhood of a residue (the nanomer) is sufficient to determine its modification status. Importantly, the application of our method yields networks of interdependent physicochemical properties of amino acids that show how these properties collaborate in establishing a given modification. We believe that the presented methods will help researchers to analyze a large class of important biological problems and will guide them in their research.
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Dahal, Gopal Prasad. "Development of Selective Inhibitors against Enzymes Involved in the Aspartate Biosynthetic Pathway for Antifungal Drug Development." University of Toledo / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1532889045486984.
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Paterson, Andrew. "Selective catalytic C-H functionalisation for drug discovery." Thesis, University of Bath, 2017. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.720659.
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This thesis details the current methods for meta-selective C-H functionalisation and contains three chapters relating to the area of ruthenium catalysed meta selective functionalisation by σ-activation. The first of which contains a published manuscript entitled “Catalytic meta-selective C-H functionalization to construct quaternary carbon centres” and describes a meta selective tertiary alkylation procedure on 2-phenylpyridine substrates. Key findings from this work provide good evidence for a radical based mechanism and proposes a catalytic cycle involving two distinct roles for the ruthenium catalyst; both in the activation of the substrate molecule and in the formation of a tertiary radical coupling partner. The second chapter contains another published manuscript entitled “Mechanistic insight into ruthenium catalysed meta-sulfonation of 2-phenylpyridine” and provides mechanistic analysis for the meta selective sulfonation of 2-phenylpyridine. Key findings from this work show through stoichiometric experiments that sulfonation occurs at the position para to the C-Ru bond formed following cyclometalation with a radical addition being implied. The work also shows that the catalytic species involved do not require an arene ligand and deuterium labelling studies identified a likely rate limiting radical sulfonation step. The final chapter contains additional work relating to the use of α-halo carbonyl coupling reagents to enable meta selective primary, secondary and tertiary alkylations. The use of a triphenylphosphine ligand source was necessary for the coupling of primary α-halo carbonyl coupling partners at the meta position. Crucially, this transformation was not possible with simple, straight-chain alkyl halides, highlighting the privileged reactivity of α-halo carbonyl coupling reagents. This work also contains experimental and computational mechanistic analysis which reveals additional support for a dual activation pathway.
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Barrett, Terrance Donald. "Relationship between ischaemia-selective drug action and antiarrhythmic efficacy." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape9/PQDD_0034/NQ38851.pdf.
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Iakovleva, Irina. "Selection of transthyretin amyloid inhibitors." Doctoral thesis, Umeå universitet, Institutionen för medicinsk kemi och biofysik, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-123939.
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Amyloidosis is a group of clinical disorders caused by the aggregation of specific proteins into abnormal extracellular deposits. Today, 31 different proteins have been linked to amyloid diseases including transthyretin-related amyloidosis (ATTR). ATTR occurs through the aggregation of either wild-type plasma protein transthyretin (TTR) or a mutated form. TTR is a homotetramer that under normal circumstances functions as a carrier of thyroxine and retinol binding protein. The aggregation cascade requires dissociation of the tetramer into monomers, and preventing this dissociation represents a potential mode of intervention. Interestingly, small molecules, referred as kinetic stabilizers, can bind to TTR’s thyroxine-binding site (TBS) and such molecules are currently being used as a therapeutic approach to impair tetramer dissociation. The efficacy of TTR stabilization is directly correlated to the binding affinity of the ligand to TBS. However, the binding of the ligand to TTR in vivo can be affected by other plasma components resulting in poor efficacy. Thus, the selectivity of ligands is an important parameter. We have designed an assay where the ability to stabilize TTR can be directly evaluated in plasma and we have investigated the stabilizing effect of nine potential TTR binders (Paper I). The results, surprisingly, revealed that the binding affinity of molecules has a poor correlation to its selectivity. However, the nature of protein-ligand complex formation can also be described by enthalpic (∆H) and entropic (∆S) energy contributions. ∆H represents the change in chemical bonds and frequently requires a higher order of orientation compared to the ∆S component, which mainly represents the hydrophobic effect via the exclusion of water. We hypothesized that ligands possessing high ΔH in binding to their co-partner would also be more specific in a complex environment such as plasma. By applying a thermodynamic analysis using isothermal titration calorimetry, we found that the selectivity in plasma correlates well with the ∆H contribution and might, therefore, be a better predictor for selectivity. Luteolin was found to be a highly selective stabilizer of TTR and was investigated further (Paper II). The ligand displayed a significant rescuing effect in both cell culture and animal models. However, luteolin undergoes rapid enzymatic degradation in the liver and this impairs its use as a potential therapeutic drug. To attempt to circumvent this issue, we modified the most exposed hydroxyl group thus rendering the molecule inert towards glucuronidation (Paper III). The substitutions resulted in higher stability in the face of hepatic degradation molecules, but they also affected the selectivity in a negative manner. The screening for new TTR stabilizers resulted in the discovery of tetrabromobisphenol A, which displayed a very high selectivity (Paper IV). This study also included a comparison with the drug Vyndaqel™ which currently is in clinically use, and showed how the dosage could be altered to acquire a better level of saturation and possibly also a better clinical effect. Taken together we present new molecules with the ability to stabilize TTR, and these can serve as scaffolds for the design of new drugs. We present a method to measure the efficacy of a TTR-stabilizing drugs in a complex matrix and as well as a way to adjust the dosage of existing drugs. We also show that the selectivity of a drug is affected by the relative proportion of ∆H and ∆S, and this is of interest for drug design in general.
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Quader, Sabina, and N/A. "Selective Synthetic Modification of Aminoglycosides for Drug Targeting to Tuberculosis." Griffith University. School of Biomolecular and Physical Sciences, 2007. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20071024.151619.
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The work presented in this thesis details the synthetic modification of the clinically important aminoglycoside antibiotics, neomycin B, paromomycin and tobramycin. We sought to modify aminoglycosides by attaching lipophilic groups, including fatty acids and steroids, with a view to improving the bacterial membrane permeability of these species, and ultimately their efficacy in the treatment of tuberculosis. Our initial synthetic strategy involved direct and specific functionalization of the singular primary hydroxyl group of the aminoglycoside antibiotic neomycin B, with lipophilic groups containing carboxylic acid functions via Mitsunobu esterification. Although, direct and selective Mitsunobu acylation of the primary hydroxyl group proved unsuccessful in the case of the pseudo tetrasaccharide neomycin B, the Mitsunobu reaction did however result in selective chemistry elsewhere in the molecule and this has been exploited for modification of the ido (ring IV) and streptamine (ring II) ring systems. Under carefully controlled conditions, the Mitsunobu reaction has been used for the selective dehydration of the ido ring, to give the talo epoxide, and, under more forcing Mitsunobu dehydration conditions, an aziridine function has been introduced into the streptamine moiety. Both the epoxide and the epoxide-aziridine neomycin building blocks were utilized as synthons in subsequent chemical transformations. Seventeen novel neomycin derivatives featuring modification of ring IV and/or ring II were obtained using this approach. Explicit structural elucidation of all the synthetic intermediates and the final products was achieved using high temperature NMR spectroscopy. Direct and specific functionalization of the singular primary hydroxyl group at the C5 position of the ribose ring (ring III) of neomycin B was achieved, via a procedure based in part on selective tripsylation of the C5III primary hydroxyl group of neomycin B reported previously, followed by subsequent displacement of the tripsyl group by azide. Terminal alkyne containing lipophilic esters were then successfully attached to the ribose residue of neomycin B via Cu(I)-mediated azide-alkyne coupling reaction. In addition to the isolation of two fortuitous, new and versatile synthons i.e. monoanhydro neomycin and bis-anhydro neomycin for modification of ring IV and ring II of neomycin, a third synthon based on neomycin framework, allowing stepwise modification of ring III and ring IV was designed and synthesized. This synthon features an epoxide function in the ido ring, and a protected amine function at the C5 position of the ribose ring. Examples of the stepwise use of this synthon for further synthetic modification of the neomycin framework were demonstrated. Fourteen novel neomycin derivatives featuring modification of ring III and /or ring IV were obtained and characterized. Regioselective Mitsunobu esterification of the single primary hydroxyl group of the pseudo trisaccharide tobramycin was utilized successfully to link a variety of hydrophobic esters with tobramycin. Nine lipophilic tobramycin derivatives with significant structural diversity were synthesised and characterized. In a preliminary study, the applicability of the Mitsunobu dehydration reaction for the regioselective formation of an epoxide ring in the ido moiety of the pseudo tetrasaccharide aminoglycoside antibiotic paromomycin system was confirmed. The regioselective ring-opening of the derived epoxide with azide at C3IV of paromomycin was also successfully demonstrated. In total, forty-two new potential aminoglycoside antibiotics have been synthesized and characterized.
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Rashid, Badrul Amini Abdul. "Development of selective solid phase extraction sorbents for drug bioanalysis." Thesis, University of Surrey, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244830.
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Yun, Hannah. "Assessment of ion-selective optical nanosensors for drug screening applications." Thesis, Massachusetts Institute of Technology, 2007. http://hdl.handle.net/1721.1/42129.
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Thesis (M. Eng.)--Massachusetts Institute of Technology, Dept. of Materials Science and Engineering, 2007."September 2007."
Includes bibliographical references (p. 67-69).
Ion channels represent an important category of drug targets. They play a significant role in numerous physiological functions, from membrane excitation and signaling to fluid absorption and secretion. An ion-channel assay system using optical nanosensors has recently been developed. This high-throughput, high-content system improves on the existing patch clamp and fluorescent dye technologies that presently dominate the ion-channel screening market. This paper introduces the nanosensor technology, reviews the current market for ion-channel assays, assesses the costs associated with the nanosensors, and evaluates their commercialization potential.
by Hannah Yun.
M.Eng.
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Quader, Sabina. "Selective Synthetic Modification of Aminoglycosides for Drug Targeting to Tuberculosis." Thesis, Griffith University, 2007. http://hdl.handle.net/10072/367086.
Full textAbstract:
The work presented in this thesis details the synthetic modification of the clinically important aminoglycoside antibiotics, neomycin B, paromomycin and tobramycin. We sought to modify aminoglycosides by attaching lipophilic groups, including fatty acids and steroids, with a view to improving the bacterial membrane permeability of these species, and ultimately their efficacy in the treatment of tuberculosis. Our initial synthetic strategy involved direct and specific functionalization of the singular primary hydroxyl group of the aminoglycoside antibiotic neomycin B, with lipophilic groups containing carboxylic acid functions via Mitsunobu esterification. Although, direct and selective Mitsunobu acylation of the primary hydroxyl group proved unsuccessful in the case of the pseudo tetrasaccharide neomycin B, the Mitsunobu reaction did however result in selective chemistry elsewhere in the molecule and this has been exploited for modification of the ido (ring IV) and streptamine (ring II) ring systems. Under carefully controlled conditions, the Mitsunobu reaction has been used for the selective dehydration of the ido ring, to give the talo epoxide, and, under more forcing Mitsunobu dehydration conditions, an aziridine function has been introduced into the streptamine moiety. Both the epoxide and the epoxide-aziridine neomycin building blocks were utilized as synthons in subsequent chemical transformations. Seventeen novel neomycin derivatives featuring modification of ring IV and/or ring II were obtained using this approach. Explicit structural elucidation of all the synthetic intermediates and the final products was achieved using high temperature NMR spectroscopy. Direct and specific functionalization of the singular primary hydroxyl group at the C5 position of the ribose ring (ring III) of neomycin B was achieved, via a procedure based in part on selective tripsylation of the C5III primary hydroxyl group of neomycin B reported previously, followed by subsequent displacement of the tripsyl group by azide.
Terminal alkyne containing lipophilic esters were then successfully attached to the ribose residue of neomycin B via Cu(I)-mediated azide-alkyne coupling reaction. In addition to the isolation of two fortuitous, new and versatile synthons i.e. monoanhydro neomycin and bis-anhydro neomycin for modification of ring IV and ring II of neomycin, a third synthon based on neomycin framework, allowing stepwise modification of ring III and ring IV was designed and synthesized. This synthon features an epoxide function in the ido ring, and a protected amine function at the C5 position of the ribose ring. Examples of the stepwise use of this synthon for further synthetic modification of the neomycin framework were demonstrated. Fourteen novel neomycin derivatives featuring modification of ring III and /or ring IV were obtained and characterized. Regioselective Mitsunobu esterification of the single primary hydroxyl group of the pseudo trisaccharide tobramycin was utilized successfully to link a variety of hydrophobic esters with tobramycin. Nine lipophilic tobramycin derivatives with significant structural diversity were synthesised and characterized. In a preliminary study, the applicability of the Mitsunobu dehydration reaction for the regioselective formation of an epoxide ring in the ido moiety of the pseudo tetrasaccharide aminoglycoside antibiotic paromomycin system was confirmed. The regioselective ring-opening of the derived epoxide with azide at C3IV of paromomycin was also successfully demonstrated. In total, forty-two new potential aminoglycoside antibiotics have been synthesized and characterized.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Biomolecular and Physical Sciences
Faculty of Science, Environment, Engineering and Technology
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Managit, Chittima. "Development of galactosylated liposome and emulsion for hepatocyte-selective drug delivery." 京都大学 (Kyoto University), 2005. http://hdl.handle.net/2433/145203.
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Kok, Robbert Jan. "Targeting of captopril to the kidney: towards selective renal ACE inhibition." [S.l. : [Groningen : s.n.] ; University of Groningen] [Host], 2008. http://irs.ub.rug.nl/ppn/.
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Hamoodi, Nehad Mehdi. "Selective and novel substrates for the assay of neutral glutathione tranferases." Thesis, University of Bradford, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.278924.
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Peng, Kevin S. M. Massachusetts Institute of Technology. "An equipment selection methodology for continuous manufacturing of small-molecule drugs." Thesis, Massachusetts Institute of Technology, 2019. https://hdl.handle.net/1721.1/122266.
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This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Thesis: S.M., Massachusetts Institute of Technology, Department of Chemical Engineering, 2019, In conjunction with the Leaders for Global Operations Program at MIT
Thesis: M.B.A., Massachusetts Institute of Technology, Sloan School of Management, 2019, In conjunction with the Leaders for Global Operations Program at MIT
Cataloged from student-submitted PDF version of thesis. "June 2019."
Includes bibliographical references (pages 87-89).
Flexible, modular, continuous manufacturing small-scale plants (MCSPs) for small-molecule drugs have been recognized as potential safe and economical solutions for pharmaceutical manufacturing. However, among the variety of equipment technologies required for an MCSP platform, there are only a few technologies that have publicly available methodologies for equipment selection. In this study, a new method and tool for computer-assisted equipment selection was developed, which use key engineering correlations and design criteria to match off-the-shelf equipment with the synthesis processes of interest. Furthermore, the tool allows simultaneous equipment selection for multiple synthesis processes to allow the identification of the most flexible MCSP assets. The long-term goal of this tool is to encompass the entire span of technologies that could be used in an MCSP skid and to serve as a communal storage location for vendor-available equipment information to facilitate collaboration and design of a mainstream continuous manufacturing (CM) system. This methodology was applied to equipment selection for the continuous manufacturing of an actual Amgen small-molecule drug substance (API) as a case study. The results from this study showed that the new tool can improve the speed at which equipment is selected and can aid the process developer in decision-making for choosing the most suitable CM asset.
by Kevin Peng.
S.M.
M.B.A.
S.M. Massachusetts Institute of Technology, Department of Chemical Engineering
M.B.A. Massachusetts Institute of Technology, Sloan School of Management
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Spann, Melissa Elizabeth Seaman John Weldon. "Bayesian adaptive designs for non-inferiority and dose selection trials." Waco, Tex. : Baylor University, 2006. http://hdl.handle.net/2104/4207.
Full text
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Fulton, Joel. "Selective interactions of nuclear receptors and cofactors: novel targets for drug discovery." Thesis, University of Nottingham, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.602958.
Full textAbstract:
Nuclear receptors (NRs) are biomedically important transcription factors that regulate gene expression by recruitment of coactivators and corepressors (cofactors) to target gene promoters. Humans express 48 different NRs.and their isoforms, approximately half of which are orphans that have no recognised ligand. NRs can interact with more than 350 known cofactor proteins, many of which are chromatin modifying enzymes. Binding of ligand induces a conformational change in the NR that stimulates or prevents the docking of cofactors. These interactions are mediated by signature motifs (LXXLL in coactivators; or LXXXIXXXI/L in corepressors) that are essential for NR/cofactor function. To allow broader understanding of cofactor selectivity, an NR LBD interaction panel was constructed consisting of seven ligand-binding and eighteen orphan NRs. Interaction studies using LXXLL motifs from the well-characterised cofactor SRCl and the lesser-studied cofactor MEDl identified distinct patterns of interaction within Class I and Class 11 subsets of NRs. Novel motifs within the developmental regulator BCLllA, with consensus Y /FSXXLXXL/Y, were also investigated, revealing selective binding to a group of related orphan NRs consisting of the NR2E/F subfamilies. This sequence was also found to be conserved in other NR cofactors such as NSDl and was again shown to facilitate interactions with this subset of orphan NRs. As highly social transcription factors, nuclear receptors form a complex and integrated dimerisation network, binding to DNA as monomers, homodimers and heterodimers. While heterodin:terisation of nuclear receptors remains poorly understood, it is known to increase the complexity of NR-mediated transcription by integrating gene networks, mUltiple ligand inputs, cofactor selectivity, and increasing competition for other heterodimeric partners. Having determined the cofactor binding preference of the NR2E/F subfamily we profiled their dimerisation, revealing diverse dimerisation properties and several interactions of interest, including novel complexes of PNR that are likely to be of physiological consequence in the retina. ii