Rozprawy doktorskie: „Drug development”

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Zhang, Huarui. "Design, synthesis and activity evaluation of novel exosome inhibitors". HKBU Institutional Repository, 2020. https://repository.hkbu.edu.hk/etd_oa/849.

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Background: Exosomes are extracellular vesicles (EVs) that produced in the endosomal compartment of most eukaryotic cells, and have observed increasing attentions over the past decades. They play important roles in cell- to-cell communications, they can carry varieties of substances, like proteins, nucleic acids and lipids, to the target cells they encounter. These cargos could influence the function of recipient cells. This novel mode of intercellular communication is found to be of critical importance to many cellular activities. However, exosomes are involved in various diseases processes. Tumor- derived exosomes could promote cancer progression, and our preliminary study indicated that exosome released from osteoclasts could inhibit bone formation. We also found that osteoarthritis (OA) progression in OA mice could be attenuated by inhibiting exosomes released by osteoclasts. Therefore, inhibition of exosome release has potential value in the treatment of diseases. The exosome release is under control by RAB27A, which is a protein involved in protein transport and signal transduction. It is reported that a compound named Nexinhib20 could selectively inhibit RAB27A, but this compound is highly toxic to RAW264.7 cells, which IC 50 is 1.5 µM. Therefore, for safety concerns, it has to be chemically modified to reduce toxicity. Aim: (1) To design and synthesize a series compounds based on the structure of Nexinhib20. (2) To evaluate the toxicity and exosome inhibiting activity of the synthesized compounds and discuss the structure-activity relationships (SAR) of them. Materials and Methods: Nexinhib20 derivatives were synthesized by aldol reaction. The cytotoxicity of these compounds was evaluated by MTT assay. The exosome inhibiting activity of these compounds was evaluated through exosome isolation and quantitation. Result: A series of compounds were synthesized and their structures were confirmed by LC-MS and NMR. The structure-activity relationships of these compounds were discussed, and the results showed that compounds A3, A23 and B2 exhibited lower toxicity compared to Nexinhib20 and strong exosome inhibiting ability. Conclusion: The results of this project indicate that A3, A23 and B2 exhibited low toxicity and good exosome inhibiting activity. Based on this, further chemical modification could be applied to develop new exosome inhibitors with better efficacy

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Larson, Joeanna Lee. "Perinatal Drug Abuse Intervention: Policy Development for Drug Screening". ScholarWorks, 2016. https://scholarworks.waldenu.edu/dissertations/2555.

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Perinatal drug abuse is becoming a profound issue facing the health and wellbeing of neonates. The community serviced by the project site, which lies within the boundaries of an Indian Reservation, suffers from perinatal drug abuse at a higher rate than state and federal averages. The purpose of this project was to provide the project site with a policy to consistently screen for perinatal drug abuse. Lave's theory of situational learning and the Sanford Way model for quality improvement framed this project. To guide policy development, data were compiled through a systematic review of current literature, national and state guidelines, state law, local tribal government, and community stakeholders. Data included: (a) studies completed in the past 10 years specifically targeting drug abuse in child-bearing aged women, with intentional exclusion of tobacco and alcohol studies; (b) prevalence of illicit drug abuse in child bearing aged women at a local, state, and national levels; and (c) local, state, and national guidelines, as well as state law, for perinatal drug abuse intervention and screening. In addition, interviews and meetings with local stakeholders were completed and their feedback was incorporated into the development of the perinatal drug abuse screening and intervention policy. To evaluate policy effectiveness, it is proposed that perinatal drug screens ordered at the project site be monitored for six months prior to and after implementation of the new policy. The desired outcome will be that providers consistently intervene with perinatal drug abuse in a non-biased fashion. This quality improvement project will create a positive social change by allowing non-biased intervention with perinatal drug abuse using evidence-based practice and by promoting nursing-driven policy development.

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Hartmann, Neil Godfried. "Intercalative drugs in cancer chemotherapy : two approaches towards drug development". Thesis, University of Cambridge, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.292983.

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Mawad, Damia Graduate School of Biomedical Engineering Faculty of Engineering UNSW. "Development of Novel hydrogels for protein drug delivery". Awarded by:University of New South Wales. Graduate School of Biomedical Engineering, 2005. http://handle.unsw.edu.au/1959.4/25221.

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Introduction: Embolic agents are used to block blood flow of hypervascular tumours, ultimately resulting in target tissue necrosis. However, this therapy is limited by the formation of new blood vessels within the tumour, a process known as angiogenesis. Targeting angiogenesis led to the discovery of anti-angiogenic factors, large molecular weight proteins that can block the angiogenic process. The aim of this research is development of poly (vinyl alcohol) (PVA) aqueous solutions that cross-link in situ to form a hydrogel that functions as an embolic agent for delivery of macromolecular drugs. Methods: PVA (14 kDa, 83% hydrolysed), functionalised by 7 acrylamide groups per chain, was used to prepare 10, 15, and 20wt% non-degradable hydrogels, cured by UV or redox initiation. Structural properties were characterised and the release of FITCDextran (20kDa) was quantified. Degradable networks were then prepared by attaching to PVA (83% and 98 % hydrolysed) ester linkages with an acrylate end group. The effect on degradation profiles was assessed by varying parameters such as macromer concentration, cross-linking density, polymer backbone and curing method. To further enhance the technology, radiopaque degradable PVA was synthesised, and degradation profiles were determined. Cell growth inhibition of modified PVA and degradable products were also investigated. Results: Redox initiation resulted in non-degradable PVA networks of well-controlled structural properties. Increasing the solid content from 10 to 20wt% prolonged the release time from few hours to ~ 2 days but had no effect on the percent release, with only a maximum release of 65% achieved. Ester attachment to the PVA allowed flexibility in designing networks of variable swelling behaviors and degradation times allowing ease of tailoring for specific clinical requirements. Synthesis of radiopaque degradable PVA hydrogels was successful without affecting the polymer solubility in water or its ability to polymerize by redox. This suggested that this novel hydrogel is a potential liquid embolic with enhanced X-ray visibility. Degradable products had negligible cytotoxicity. Conclusion: Novel non-degradable and radiopaque degradable PVA hydrogels cured by redox initiation were developed in this research. The developed PVA hydrogels showed characteristics in vitro that are desirable for the in vivo application as release systems for anti-angiogenic factors.

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Fagnan, David Erik. "Analytics for financing drug development". Thesis, Massachusetts Institute of Technology, 2015. http://hdl.handle.net/1721.1/98572.

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Thesis: Ph. D., Massachusetts Institute of Technology, Sloan School of Management, Operations Research Center, 2015.
This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Cataloged from student-submitted PDF version of thesis.
Includes bibliographical references (pages 133-139).
Financing drug development has a particular set of challenges including long development times, high chance of failure, significant market valuation uncertainty, and high costs of development. The earliest stages of translational research pose the greatest risks, which have been termed the "valley of death" as a result of a lack of funding. This thesis focuses on an exploration of financial engineering techniques aimed at addressing these concerns. Despite the recent financial crisis, many suggest that securitization is an appropriate tool for financing such large social challenges. Although securitization has been demonstrated effectively at later stages of drug development for drug royalties of approved drugs, it has yet to be utilized at earlier stages. This thesis starts by extending the model of drug development proposed by Fernandez et al. (2012). These extensions significantly influence the resulting performance and optimal securitization structures. Budget-constrained venture firms targeting high financial returns are incentivized to fund only the best projects, thereby potentially stranding less-attractive projects. Instead, such projects have the potential to be combined in larger portfolios through techniques such as securitization which reduce the cost of capital. In addition to modeling extensions, we provide examples of a model calibrated to orphan drugs, which we argue are particularly suited to financial engineering techniques. Using this model, we highlight the impact of our extensions on financial performance and compare with previously published results. We then illustrate the impact of incorporating a credit enhancement or guarantee, which allows for added flexibility of the capital structure and therefore greater access to lower costing capital. As an alternative to securitization, we provide some examples of a structured equity approach, which may allow for increased access to or efficiency of capital by matching investor objectives. Finally, we provide examples of optimizing the Sortino ratio through constrained Bayesian optimization.
by David Erik Fagnan.
Ph. D.

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Voyi, Kuku Vinolia Vuyelwa. "Development of an antirheumatic drug". Doctoral thesis, University of Cape Town, 1988. http://hdl.handle.net/11427/17187.

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Includes bibliographical references.
The diamino-diamide ligands have been investigated in an attempt to develop an antirheumatic drug. The ligands N,N'-di-(2-dimethylamino)ethyloxamide and N,N'di-(2-diethylamino)ethyloxamide, were synthesised and characterised using the physical techniques, NMR, mass- and infrared spectrometry. The stability constants of the complexes of Mg, Ca, Zn and several first transition metal-ions with the ligands were determined potentiometrically. The solution conformation of the CuII complexes were determined using visible spectrophotometry. Finally the physico-chemical studies were carried out. Firstly by studying the interaction of the copper complex with albumin at the physiological pH 7.4 using visible spectrophotometry. Secondly by determining the superoxide dismutase activity of the ligand by reduction of nitrobluetetrazolium using visible spectrophotometry. Lastly the ligands and the carr, CuII, MgII and ZnII metalions were monitored in vitro using the computer blood plasma model.

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Alkhaldi, Abdulsalam Abdulhadi. "Drug development against kinetoplastid parasites". Thesis, University of Glasgow, 2012. http://theses.gla.ac.uk/3637/.

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Human African trypanosomiasis and leishmaniasis are caused by parasites belonging to the genera Trypanosoma and Leishmania, respectively. Significant numbers of people are affected by these diseases worldwide, which are fatal if untreated. Animals can also be infected, posing agricultural and economic hindrances, especially in poor countries. Although chemotherapy can be used for treatment, many problems are associated with it, including drug toxicity, resistance, lack of guaranteed supply, and high treatment cost. Therefore, there is an urgent need for new treatment approaches. Here, we aim to examine the in vitro efficacy of curcumin and phosphonium compounds against these parasites, assay their toxicity to human kidney cells in vitro, and investigate the mechanism of antiparasite activity of curcumin. The Alamar blue assay was used to test 158 curcumin analogues against Leishmania major promastigotes and Leishmania mexicana promastigotes and axenic amastigotes to obtain in vitro EC50 values. Many curcumin compounds such as AS-HK122 and AS-HK126 exhibited anti-leishmanial activities similar to or better than the current clinical drug pentamidine. Similarly, EC50 values of 83 phosphonium compounds against Trypanosoma brucei brucei bloodstream forms were determined. More than 20% of the tested compounds were found to be more active than the standard veterinary drug diminazene aceturate. Multi-drug resistant strains were used to determine that there is no cross-resistance between the tested compounds and the diamidine or melaminophenyl arsenical classes of trypanocides. Structure activity relationship (SAR) analysis revealed that mono-O-demethylated curcumin compounds showed 10-fold higher activity against the parasites than curcumin. The addition of one or two pentyl pyridinium (C10H15N) groups on specific positions of the aromatic ring also increased the activity of these compounds. Furthermore, curcumin compounds with an isoxazole ring instead of the diketo motif showed higher activity and the lowest EC50 values. Similarly, pentyl bromide (OC5H10Br) substitutions on the phenyl rings improved the antiparasitic activity. Curcuminoids with trienone linkers showed increased antiparasitic activity against all parasites tested. Eighty-three phosphonium analogues were tested against T. brucei brucei. SAR analysis indicated that the bulky substituents surrounding the bisphosphonium cations led to strong antiparasitic activity while the nature of the linker had less effect on the activity. Some monophosphonium analogues registered the lowest EC50 values of all the phosphonium compounds. The toxicity of the curcumin and phosphonium analogues to HEK cells was analysed in vitro. All curcumin and phosphonium compounds demonstrated lower toxicity to HEK cells than to the parasites. Of the 83 phosphonium compounds, 60 displayed >200-fold in vitro selectivity index (SI). We also investigated the mode of antiparasitic activity of curcumin compounds. Preliminary toxicity tests had revealed that AS-HK014 caused rapid depletion of glutathione content in rat hepatocytes. Therefore, we tested AS-HK014 activity in the presence of different concentrations of L-glutathione, and AS-HK014 activity was found to decrease with increased L-glutathione concentrations, strongly suggesting that glutathione reacted with the active compound. Indeed, a chemical adduct was observed between the two compounds and identified through mass spectrometry. A trypanosome cell line (TA014) adapted to AS-HK014 was produced. TA014 and wild-type T. brucei brucei were treated with AS-HK014 and compared with each other and with untreated controls. The glutathione and trypanothione levels were lower in the treated WT cells than in the untreated cells. However, there was no change in the glutamate, ornithine, or spermidine levels, providing no evidence for the inhibition of trypanothione synthesis, suggesting that the effect is probably not metabolic but chemical. AS-HK014 did not significantly affect thiol levels in TA014; this might reflect a higher level of trypanothione synthesis through increased glutathione synthetase (GS) and/or γ-glutamylcysteine synthetase (γ-GCS) expression. Therefore, we analysed the protein levels using western blotting, and sequenced the encoding genes in both WT and TA014 to identify any mutations in the open reading frames (ORFs). However, we found no changes in the GS and γ-GCS protein levels in resistant trypanosomes and no mutations were found in the GS and γ-GCS ORFs. It is clear that the resistance is to the reactive enone motif of AS-HK014 rather than to curcumin and curcuminoids in general, since TA014 only displayed resistance to AS-HK014 analogues bearing the enone motif while sensitivity to curcumin remained unchanged, confirming that this motif is responsible for the higher activity of AS-HK014 compared to curcumin. The effects of bisphosphonium analogues on T. brucei brucei bloodstream forms were investigated to identify the target. All tested analogues rapidly reduced the T. brucei brucei mitochondrial membrane potential Ψm and decreased the intracellular ATP level after one hour of incubation, suggesting that the compounds may be targeting the mitochondria. The intracellular Ca2+ levels increased gradually after eight hours, suggesting that the damaged mitochondria are unable to retain the stored Ca2+ as their membrane potential dissipates. We also studied the trypanosome cell cycle after incubating the parasites with bisphosphonium compounds. The cell cycle defects became apparent after eight hours of incubation: DNA synthesis could not be initiated, leading to a dramatic reduction of cells in the S phase. This result was also confirmed by fluorescence microscopic assessment of DNA configuration. After eight hours of incubation with the bisphosphonium compound CD38, the number of 2K1N cells significantly decreased as compared with the control. There may be a causal relationship between mitochondrial damage and cell cycle defects. Transmission electron microscopy images of the cells obtained after 12 h of exposure to CD38 also revealed the presence of mitochondrial damage. We tested whether bisphosphonium compounds can induce programmed cell death in trypanosomes. A TUNEL assay was used to detecting DNA fragmentation; the results showed increased DNA fragmentation after 24-h treatment with two different bisphosphonium compounds, CD38 and EFpI7. This result indicates is consistent with apoptosis occurring in treated cells but there was no evidence suggesting that bisphosophonium-induced cell death in trypanosomes is dependent on new protein synthesis. In conclusion, curcumin and phosphonium analogues exhibit promising antiparasitic activity, and some analogues could be optimised for in vivo evaluation. Further investigations on the site of action of phosphonium compounds in the mitochondrion are in progress.

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Mavridis, Lazaros. "High throughput virtual drug screening using spherical harmonic molecular surface representations". Thesis, Available from the University of Aberdeen Library and Historic Collections Digital Resources, 2009. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?application=DIGITOOL-3&owner=resourcediscovery&custom_att_2=simple_viewer&pid=25936.

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Wang, Shining. "DRUG DEVELOPMENT OF TARGETED ANTICANCER DRUGS BASED ON PK/PD INVESTIGATIONS". Diss., Temple University Libraries, 2008. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/2535.

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Pharmaceutics
Ph.D.
EGFR inhibitors, such as gefitinib, are examples of targeted anticancer drugs whose drug sensitivity is related to gene mutations that adds a pharmacogenetic [PG] dimension to any pharmacokinetic [PK] and pharmacodynamic [PD] analysis. The goal of this project was to characterize the PK/PD properties of gefitinib in tumors and then apply these results to design rational drug design regimens, and provide a foundation for future studies with EGFR inhibitors. Progressions of in vitro and in vivo studies were completed to understand the PK and PD behavior of gefitinib. In vitro cytotoxicity assays were first conducted to confirm the gefitinib sensitivity differences in a pair of human glioblastoma cell lines, LN229-wild-type EGFR and LN229-EGFRvIII mutant, an EGFR inhibitor-sensitizing mutation. Subsequent in vitro PD studies identified phosphorylated-ERK1/2 (pERK) as a common PD marker for both cell lines. To describe the most salient features of drug disposition and dynamics in the tumor, groups of mice bearing either subcutaneous LN229-wild-type EGFR or LN229-EGFRvIII mutant tumors were administered gefitinib at doses of 10 mg/kg intravenously (IV), 50 mg/kg intraarterially (IA) and 150 mg/kg orally (PO). In each group, gefitinib plasma and tumor concentrations were quantitated, as were tumoral pERK. Hybrid physiologically-based PK/PD models were developed for each tumor type, which consisted of a forcing function describing the plasma drug concentration-profile, a tumor compartment depicting drug disposition in the tumor, and a mechanistic target-response PD model characterizing pERK in the tumor. Gefitinib showed analogous PK properties in each tumor type, yet different PD characteristics consistent with the EGFR status of the tumors. Using the PK/PD model for each tumor type, simulations were done to define multiple-dose regimens for gefitinib that yielded equivalent PD profiles of pERK in each tumor type. Based on the designed PK/PD equivalent dosing regimens for each tumor type, gefitinib 150 mg/kg PO qd × 15 days and 65 mg/kg PO qd × 15 days multiple-dose studies were conducted in wild-type EGFR and EGFRvIII mutant tumor groups, respectively. In each tumor group, gefitinib plasma and tumor concentrations were measured on both day 1 and day 15, as were tumoral amounts of pERK. Different from single-dose model simulations, gefitinib showed nonlinear PK property in the wild-type tumor due to the down-regulation of membrane transporter ABCG2. Moreover, acquired resistance of tumoral pERK inhibition was observed in both tumor types. Nevertheless, gefitinib had an analogous growth suppression action in both tumor groups, supporting the equivalent PD dosing strategy. Overall, single-dose gefitinib PK/PD investigations in a pair of genetically distinct glioblastomas facilitated the development of hybrid physiologically-based PK/PD models for each tumor type, and further introduced a novel concept of PK/PD equivalent dosing regimens which could be applied in novel drug development paradigms. Preliminary multiple-dose gefitinib studies revealed more complex PK/PD characteristics that needed to be further explored.
Temple University--Theses

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Alavi, Hajar Karimi. "Development of mechanistic mathematical models for gene-mediated drug-drug interactions". Thesis, University of Manchester, 2016. https://www.research.manchester.ac.uk/portal/en/theses/development-of-mechanistic-mathematical-models-for-genemediated-drugdrug-interactions(b38da88a-bb2a-4667-9809-21a09c8feeeb).html.

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The glucocorticoid receptor (GR) is a member of the nuclear hormone receptors family and has been shown to exert significant effects on the induction of cytochrome P450 (CYP) enzymes responsible for the metabolism of many xenobiotics. CYP3A4/5 and CYP2C9 are important CYP enzymes which metabolise more that 60% of drugs. Induction or inhibition of the enzymatic activity and the levels of these enzymes can have significant effects on drug metabolism. Understanding the role of GR and other nuclear receptors, pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), in the mechanisms effecting CYP3A4/5 and CYP2C9 levels and activity can aid in the development of in vitro and in vivo models which have become a target for scientists in the clinic and the industry. The commonly prescribed synthetic glucocorticoid (GC) drug, dexamethasone (Dex), can induce GR, PXR and CAR and was used in this study to analyse its effects on the CYP enzymes studied. The hypothesis of this project was that changes in CYP3A4/5 and CYP2C9 gene expression affect drug metabolism and changes in gene expression of these CYP enzymes was under GR, PXR and CAR control, thus affecting the concentration and therapeutic activity of drugs metabolized by these enzymes during chronic use of GCs in conditions such as rheumatoid arthritis and asthma. This study aimed to measure mRNA, protein, ROS and enzymatic activity levels in human HepG2 hepatocytes treated with Dex for 120 h and analyze the results for various time points to produce a mathematical model. Our study has shown that changes in mRNA, protein and enzymatic activity levels of CYP3A4/5 and CYP2C9 in HepG2 cells were induced by Dex at sub-micromolar (0.1 µM) and supra-micromolar (1.5 mM) concentrations. The induction of CYP3A4/5 and CYP2C9 enzymes during 120 h treatment with Dex may be affected by the NRs studied; GR, phosphorylated GR, PXR and CAR protein levels were also shown to be induced by Dex. The efflux transporter, P-gp’s protein levels were also induced by 0.1 µM Dex, highlighting the importance of considering bioavailability of other drugs co-administered with Dex. The results of some of these laboratory experiments have been used to produce mechanistic mathematical models by MATLAB software with reference to previous studies in rats concentrating on the effects of steroids on GR. The models developed were not effective at the lower Dex concentration of 0.1 µM but were better modelled at the higher Dex concentration of 1.5 mM. The basic mechanistic models developed using HepG2 cells in this study can be utilised to design and conduct drug-drug interaction (DDI) analyses of the induction of CYP3A4/5 and CYP2C9 in other human liver cells and starting pre-clinical studies in animals to aid in drug development.

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Pavuluri, Nina. "Development and evaluation of drug-admicelle systems for poorly soluble drugs : a novel surfactant templated drug delivery platform /". Full text available from ProQuest UM Digital Dissertations, 2008. http://0-proquest.umi.com.umiss.lib.olemiss.edu/pqdweb?index=0&did=1781035201&SrchMode=1&sid=1&Fmt=2&VInst=PROD&VType=PQD&RQT=309&VName=PQD&TS=1258661510&clientId=22256.

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Thesis (Ph.D.)--University of Mississippi, 2008.
Typescript. Vita. Major advisor: John O' Haver "June 2008." Includes bibliographical references (leaves 120-163). Also available online via ProQuest to authorized users.

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Strobeck, Matthew W. (Matthew William) 1972. "The drug development process : evaluation of PDUFA I/II and investigation into reducing drug development times". Thesis, Massachusetts Institute of Technology, 2004. http://hdl.handle.net/1721.1/28592.

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Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology; and, (S.M.)--Massachusetts Institute of Technology, Engineering Systems Division, Technology and Policy Program, 2004.
Includes bibliographical references (p. 59-61).
Published findings report that it takes approximately eight years to bring a novel drug to market at an average cost of $800 million. Over the last ten years, the Food and Drug Administration (FDA) has helped to reduce the time from filing a new drug application (NDA) to granting marketing approval (i.e. the approval phase). However, there has been no alteration in the time required to progress from an investigational new drug application (IND) to an NDA filing (i.e. the clinical phase) over this same period. Since approval times began to decrease upon the initiation of the Prescription Drug User Fee Act (PDUFA), in this thesis I analyze the impact of PDUFA and calculate its benefits to companies. Due to the importance of getting new drugs to the market faster, I also investigate why there has been no significant change in the time required to test a drug clinically, and attempt to identify steps that could be taken to improve the clinical trial process. To investigate this, I evaluated ways in which the FDA and industry can work together to reduce clinical development times, without compromising safety. The results from this study show that PDUFA has had a significant impact on reducing approval times. More importantly, I determined that the direct costs of PDUFA are small in irmlparison to its benefits. In addition, my analysis of the early clinical phases (pre-clinical to Phase II) of drug benefits. In addition, my analysis of the early clinical phases (pre-clinical to Phase II) of drug development has revealed potential steps both the FDA and industry can take to facilitate a more efficient process for assessing the safety and efficacy of drugs. Thus, this study represents an important step towards improving the development of medicines for the world.
by Matthew W. Strobeck.
S.M.

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Lee, Anna. "Bioinformatics approaches towards facilitating drug development". Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=96984.

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Drug development is currently a time-consuming, costly and challenging process. The process typically starts with the identification of a therapeutic target for a given disease. A therapeutic target is some biological molecule and the binding of compounds to target molecules is expected to cause a desired therapeutic effect. That is, target binding compounds have the potential to become drug candidates. However, there is a tendency for many drug candidates to fail during clinical trials, and consequently, very few candidates become approved new drugs. This trend suggests that the early stages of drug development should be improved to provide better drug candidates.The reasons for which a drug candidate may fail during clinical trials include unacceptable toxicity and insufficient efficacy observed in humans. These reasons suggest that the assessments of a compound during the early stages of drug development often inaccurately predict the effect of the compound in humans. One of the main goals of systems biology is to accurately predict how a given biological system responds to perturbations, e.g. treatment with a compound. This suggests that systems biology can help address challenges in drug development. However, there are currently gaps in our knowledge of systems. Here we use machine learning techniques to exploit existing systems data towards filling in these gaps. In particular, we developed a method that uses the occurrences of motifs in protein sequences to predict kinase-substrate interactions. We also developed a method that uses gene expression, protein-protein interaction and phenotype data to predict genetic interactions. These predicted interactions can facilitate the identification of potential therapeutic targets. Ultimately, a better selection of therapeutic targets should lead to better drug candidates.We also address the challenge of developing combinatorial therapies. Despite the fact that combinatorial therapies are advantageous, the scale of the experiments required to search for desirable chemical combinations is currently prohibitive. We therefore developed a method that uses system response data to predict chemical synergies towards facilitating the development of combinatorial therapies.Overall, this thesis shows how computational prediction in a systems biology framework can be used to facilitate and expedite the early stages of drug development.
Le développement des médicaments est actuellement un processus coûteux, difficile, et qui prend beaucoup de temps. Le processus commence généralement par l'identification d'une cible thérapeutique pour une maladie spécifique. Une cible thérapeutique est une molécule biologique et l'attachement des composés aux molécules cibles est supposé causer un effet thérapeutique. Donc, les composés qui attachent aux cibles ont le potentiel de devenir des candidats médicaments. Toutefois, beaucoup de candidats médicaments ont tendance à échouer pendant les essais cliniques, et par conséquence, très peu de candidats deviennent nouveaux médicaments approuvés. Cette tendance suggère que les premières étapes du développement de médicaments doit être amélioré afin de fournir des candidats médicaments de meilleure qualité.Les raisons pour lesquelles un candidat médicament peut échouer pendant les essais cliniques incluent une toxicité inacceptable et une éfficacité insuffisante observés chez les humains. Ces raisons suggèrent que les évaluations d'un composé pendant les premières étapes du développement de médicaments mal prédirent l'effet du composé chez les humains. Un des principaux objectifs de la biologie des systèmes est de prédire avec précision comment un système biologique répond à des perturbations, par exemple, un traitement avec un composé. Ceci suggère que la biologie des systèmes peut aider à aborder les défis du développement de médicaments. Toutefois, il existe actuellement des lacunes dans notre connaissance des systèmes. Ici, nous utilisons des techniques d'apprentissage automatique pour exploiter l'information existantes des systèmes pour combler ces lacunes. En particulier, nous avons développé une méthode qui utilise des occurrences des motifs dans les séquences de protéine pour prédire des interactions kinase-substrat. Nous avons aussi développé une méthode qui utilise d'expression des gènes, des interactions entre les protéines et d'information des phénotypes pour prédire des interactions génétiques. Ces interactions prédites peuvent faciliter l'identification des cibles thérapeutiques potentielles. En fin de compte, une meilleure sélection des cibles thérapeutiques devrait entraîner des candidats médicaments de meilleure qualité.Nous avons aussi abordé le défi de développer des thérapies combinatoires. Malgré le fait que les thérapies combinatoires sont avantageuses, l'ampleur des expériences nécessaires à la recherche de combinaisons chimiques souhaitables est actuellement prohibitif. Donc, nous avons développé une méthode qui utilise d'information de réponse des systèmes pour prédire des synergies chimiques en vue de faciliter le développement de thérapies combinatoires.Dans l'ensemble, cette thèse montre comment de calcul de prédiction dans une structure de biologie des systèmes peut être utilisés pour faciliter et accélérer les premières étapes du développement de médicaments.

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郭心鈴 i Sum-ling Kwok. "New drug development in breast cancer". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B41710381.

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Thiers, Fabio Albuquerque. "The globalization of clinical drug development". Thesis, Massachusetts Institute of Technology, 2006. http://hdl.handle.net/1721.1/35556.

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Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2006.
Includes bibliographical references (p. 54-58).
Industry-sponsored clinical research of investigational drugs (also called clinical development) has traditionally been carried out in relatively developed countries in the North American, Western European, and Pacific regions. However, lately it has been widely reported that clinical trials starting now are becoming increasingly diffused globally, with significant growth of activity in so-called emerging economies in Eastern Europe, Latin America, and Southeast Asia. This change in location of clinical development activities has numerous implications for patients, health care providers, pharmaceutical companies, regulatory agencies and governments around the globe. Even though there is much debate about the topic, a public systematic quantitative assessment of the current status of the globalization of clinical drug development phenomenon is lacking. The objective of this thesis research is to provide such objective quantification while addressing some issues that are currently in active discussion. This thesis documents that the participation of emerging countries is still relatively small (13%) and they most commonly participate in very large (involving more than five countries) phase Ilb or III trials.
(cont.) Albeit perceived as small, this participation is growing at a rapid pace (23% average annual growth rate) and the number of clinical sites of global clinical trials located in all emerging countries (11,038) is comparable with the sum of Germany, France, U.K., and Italy (11,061). Eastern European and Latin American countries have the greatest participation in clinical trials among emerging countries, but Southeast Asia is the region that is experiencing fastest growth. Meanwhile, Western Europe has experienced negative average annual growth of -8%, and North America has seemingly been stable. This thesis discusses findings and key drivers behind the globalization process. I also consider the argument that the sustainability of this model will depend on stringent protection of patients in these emerging countries and continued development of these nations, with eventual creation of an attractive market for pharmaceutical products. The extension of this process of globalization of clinical trials, if coupled with substantial improvements in health care delivery and research capacity in these emerging economies, has the potential of revolutionizing medical product development within the next two decades.
by Fabio Albuquerque Thiers.
S.M.

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Kwok, Sum-ling. "New drug development in breast cancer". Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B41710381.

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Sanghvi, Tapan. "Formulation development of anticancer drug: FB642". Diss., The University of Arizona, 2004. http://hdl.handle.net/10150/289236.

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Carbendazim (methyl-2-benzimidazolecarbamate), a well known anti-fungal agent that may have significant anti-cancer activity, is a poorly water-soluble ampholyte. Unfortunately its projected oral dose up to hundred mg per day is far greater than its water solubility of 6 μg/ml. The overall aim of this research was to conduct preformulation studies and develop therapeutically viable oral and parenteral formulations. The solubility of carbendazim was altered by using both solute and solvent modification approaches. The solvent modification was carried out by investigating the solubilization of carbendazim by pH in combination with cosolvents, surfactants or complexants. At pH 7 the total drug solubility is 6.11 ± 0.45 μg/ml which increases by 1 to 7 fold with cosolvent, surfactant or complexant. However, at pH 2 the solubility increases by 400 times and at pH 1.3 over 3000 times. Both cosolvents and non-ionic surfactants have a negligible effect on the total drug solubility at pH 2, whereas the total drug solubility increases by combining pH 2 with anionic surfactants or complexants. The solute modification was accomplished by preparing different salts of carbendazim. In all six different salts, viz., hydrochloride dihydrate, phosphate, hemisulfate hydrate, mesylate, besylate, and tosylate were prepared. Their structures were determined using single crystal x-ray diffraction. The developability attributes (i.e. hygroscopicity, thermal behavior, aqueous solubility, solid state stability, and dissolution rate) of these compounds were evaluated. The dissolution studies showed that all the salts had better dissolution rate than the free base, the mesylate salt been the best. Based on the preformulation studies, two formulations were chosen for oral dosing in mice. The proposed oral formulation of 9.4 mg/ml carbendazim at pH 1 in phosphate buffer and 20% SBEβCD phosphate buffer, respectively, did not precipitate on in vitro static serial dilution with water and seven up. However, the formulation containing only phosphate buffer showed activity in mice by significantly reducing the tumor growth in B-16 melanoma injected mice. Also, it gave active blood levels, which were comparable to IV dosing.

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Cipriano, Sónia Domingues. "Pharmaceutical development: galenical development of a generic drug product". Master's thesis, Universidade de Aveiro, 2017. http://hdl.handle.net/10773/18818.

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Mestrado em Biomedicina Farmacêutica
O desenvolvimento de genéricos reveste-se de grande complexidade pela demanda de qualidade associada a qualquer produto farmacêutico acrescida da complexa interpretação de situação jurídica (patentes), da seleção de um vasto número de moléculas e tecnologias que trarão um claro custo-benefício e dos exigentes prazos para as colocar em mercados, muitas vezes com diferentes requisitos regulatórios. Esta tese irá providenciar uma visão geral sobre um método standard numa indústria de desenvolvimento farmacêutico. O presente trabalho tem como objetivo descrever os pontos gerais de um desenvolvimento galénico, seguido por exemplos práticos, de forma a avaliar um projeto desde o seu estado conceptual até à fase de ensaio clínico. De forma a dar uma visão clara de desenvolvimento galénico numa instalação de estado da arte, este trabalho irá abordar processos usados na análise da viabilidade de projetos, formulação, processos de fabrico e submissão de dossiers de produtos investigacionais.
The development of generics is a very complex area due to the demand for quality associated to any pharmaceutical product added to the complex interpretation of legal situation (patents), the selection of a large number of molecules and technologies that will bring a clear cost-benefit and the demanding deadlines for placing them in markets, often with different regulatory requirements. This thesis will provide a general view of a standardized method used in a pharmaceutical development company. The present work intends to describe the general points of the galenical development followed by practical examples of this process, evaluating the project from its initial conceptual phase until clinical trial. In order to portrait a clear picture of the galenical development on a state of the art facility, the work will access current processes used for project viability analysis, formulation, manufacturing processes and IMPD submission

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Alali, Khaled Y. A. A. "Development of National Drug Policy in the State of Kuwait". Thesis, University of Bradford, 2016. http://hdl.handle.net/10454/16793.

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This Thesis examines the benefits and usefulness of a National Drug Policy (NDP) for the developing of the Health Care System in Kuwait. The NDP is one of the most important structures of the Health System which can lead to improved health services by establishing guidelines, proposals and directives to organize, structure and regulate health legislation; it is of help to ensure the availability of quality, safety and efficacy in using medicines and it can reduce the irrational use of medicines. The NDP is a frame work between the government, schools and universities, media, health professionals, pharmaceutical industries and companies and public. It is cooperation between the public and private sectors to achieve the goal of access to good quality medicines for all. However there are many key factors which need to be examined before the National Drug Policy is introduced and these are considered the baseline for establishing a good policy, and includes; selection of essential drugs, affordability of drugs, drug financing, supply management, drug regulation, rational use of drugs, drugs registration, purchasing of drugs, health research and human resource development. During this research study from 2012 – 2015 several visits to the public and private health areas, were undertaken. At this time there were discussions with 121 health professionals and data was collected and this indicated that in Kuwait there are no such policies. This is despite the availability of financial means, specialized human resources and the existence of the ministerial decisions and regulations governing the health sector in both public and private, whether hospitals, health centers, pharmacies and health departments. In addition it is suggested that the process of a good NDP should be built around 3 main components which includes: 1.Development, 2. Implementation and 3. Monitoring and Evaluation. Therefore the establishing of a NDP without implementation and monitoring is not enough and does not achieve the desired results. The aim of this Thesis is to establish a NDP in the State of Kuwait. This policy is necessary for the State of Kuwait to ensure development an improvement of the Health Care System and ensure better health for population.

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Sostelly, Alexandre. "Mechanistic model-based drug development in the management of anticancer drugs resistance". Thesis, Lyon 1, 2012. http://www.theses.fr/2012LYO10203.

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La résistance aux chimiothérapies anticancéreuses constitue un problème majeur dans la prise en charge du cancer. Les transporteurs d'efflux contribuent à ce phénomène de résistance en altérant l'accumulation intracellulaire des cytotoxiques. Dans le passé, l'inhibition du transporteur d'efflux P-gp n'a pas permis de surmonter ce phénomène notamment à cause du manque de méthodes adéquates pour identifier et quantifier la pharmacologie des inhibiteurs d'efflux. Récemment de nouveaux inhibiteurs de BCRP, l'un des derniers transporteurs d'efflux découverts, ont été synthétisés permettant de retester l'intérêt de l'inhibition de ces transporteurs dans la prise en charge de la résistance aux anticancéreux. Néanmoins, afin d'éviter les mêmes écueils que lors du développement des inhibiteurs de P-gp, il est nécessaire d'utiliser d'autres approches telles que la modélisation mathématique dès le début du développement préclinique de ces inhibiteurs. Cette thèse a pour but de montrer les bénéfices de la modélisation et de la simulation dans le développement préclinique des inhibiteurs de transporteurs d'efflux et plus largement dans le développement des molécules anticancéreuses. L'exemple utilisé au travers de ce travail concerne l'étude de l'interaction entre l'irinotecan, un cytotoxique largement utilisé dans le traitement du cancer colorectal, et le MBLI87, un nouvel inhibiteur de BCRP. Deux principaux axes ont été abordés dans ce travail : - Le développement de modèles (semi-) mécanistiques à effets mixtes pour identifier et quantifier les facteurs impactant l'efficacité de la combinaison irinotecan-MBLI87 - Le développement de modèles d'inhibition de la croissance tumorale à effets mixtes pour évaluer précocement ce type d'interaction de traitements et pour optimiser la réponse tumorale. Les résultats obtenus avec l'approche de modélisation ont permis d'identifier certains des mécanismes tumoraux impactant l'efficacité des inhibiteurs de transporteur d'efflux. De plus cette approche s'est révélée supérieure aux approches classiques dans l'évaluation de ces molécules et dans l'optimisation de la réponse tumorale démontrant la puissance de la modélisation et de la simulation comme outil de développement des molécules anticancéreuses
Anticancer drug resistance is a major issue in the management of cancer disease. Efflux transporters contribute to the multidrug resistance by altering the intracellular disposition of cytotoxic drugs. In the past, the inhibition of P-gp efflux transporter essentially failed because of the lack of adequate methods to identify their mechanisms of action. Recently, new inhibitors of BCRP, one of the latest efflux transporter that have been discovered, have been developed that allow re-testing the multidrug resistance inhibition through efflux inhibition. Nevertheless, to avoid the same issues of development as for P-gp inhibitors, new methods have to be used. This PhD work aims to demonstrate the benefits of mechanistic models to support the development of efflux transporter inhibitors and more generally of oncology compounds through two axes: - The development of mechanistic models of the interaction between cytotoxic and efflux transporter inhibitors - The development of quantitative tumour growth inhibition models to early evaluate oncology compounds and optimize patients’ response The results obtained with this approach allow the identification of key mechanisms of efflux transporter inhibitors and demonstrate the power of modelling and simulation to support oncology drug development

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21

Mohiddin, Syed Basha. "Development of novel unsupervised and supervised informatics methods for drug discovery applications". Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1138385657.

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Schreiber, Kimberly C. M. "Assay development for use in drug discovery against Bovine Trichomoniasis". Scholarly Commons, 2007. https://scholarlycommons.pacific.edu/uop_etds/650.

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Bovine trichomoniasis is a venereal disease that affects cattle. The causative agent of this disease is Tritrichomonas foetus, a flagellated protozoan. There is no current FDA approved treatment for this disease. The purpose of this study was to develop new compound screening assays that will make the discovery of new compounds faster and more accurate. The CellTiter-Glo Luminescent Cell Viability Assay, a high throughput screening (HTS) assay from Promega, was found to be as affective at measuring cytotoxicity as traditional assaying techniques. For the first time. preen florescent protein. a reporter gene used in cell viability assavs was successfully transformed into T. foetus for use in HTS systems. This study also identified new compounds that can potentially be used as new treatments for this disease.

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Pieters, Toine. "Biology meets drug development the biography of a 'miracle' drug, the interferons /". [Maastricht : Maastricht : Universiteit Maastricht] ; University Library, Maastricht University [Host], 1999. http://arno.unimaas.nl/show.cgi?fid=6879.

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Patel, Fadheela. "Development of a cost-effective drug sensitivity test for multi-drug resistant and extensively drug-resistant tuberculosis". Thesis, Cape Peninsula University of Technology, 2010. http://hdl.handle.net/20.500.11838/1496.

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Thesis (MTech (Biomedical Technology))--Cape Peninsula University of Technology, 2010
The World Health Organisation estimates that nine million people are infected with tuberculosis (TB) every year of which ninety-five percent live in developing countries. Africa has one of the highest incidences of TB in the world. but few of its countries are equipped to diagnose drug-resistant TB. This study aimed to develop a robust. yet simple and cost-effective assay. which would require minimal sophisticated instrumentation and specialised personnel that would make drug sensitivity screening for multi-drug resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) accessible to resource-poor high-burden settings. A four-quadrant colorimetric agar plate method was developed which showed good specificity (97.3%-100%) and sensitivity (77.8%-100%) compared to the polymerase chain reaction (PCR) method used as gold standard. Agreement between the methods. using Simple Kappa Coefficients. ranged between very good and excellent. all with high statistical significance (P < 0.0001). The currently used BACTEC MGIT SIREN sensitivity assay coupled with the E-test® strip method. as routinely used in the TB reference laboratory. was compared and showed excellent comparison with the newlydeveloped plate method. for each antibiotic tested. as well as the resultant monoresistant, MDR- or XDR-TB diagnoses. Moreover. the new method was found to be extremely cost-effective. priced at half the cost of a peR assay. These four quadrant plates. with a colorimetric indicator and selected antibiotics. can be considered as an economic altemative or a complimentary method for laboratories wishing to reduce the cost and complexity for TB drug sensitivity testing. Routine diagnostic testing would thus be made more accessible and affordable to laboratories that are not presently diagnosing drug resistant TB. therefore enhancing case detection and treatment in the resource-poor settings hardest hit by this curable disease.

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Chieng, Heng Liang Norman, i n/a. "Amorphous drug preparation using ball milling". University of Otago. School of Pharmacy, 2008. http://adt.otago.ac.nz./public/adt-NZDU20081209.162001.

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Polymorphism and crystallinity are now recognised as important issues in drug development. This is shown by the increased amount of research in this area over recent years. In pharmaceutical development milling is an important unit operation for size reduction to improve powder handling, processing and dissolution rate. The aim of this thesis was to investigate the effect of ball milling (and cryo-milling) on the solid state properties, including amorphous drug formation, of pharmaceutical solids. Milling was carried out using an oscillatory ball mill (Mixer Mill MM301, Retsch GmbH & Co., Germany). In cryo-milling the milling jars were immersed in liquid nitrogen for three min before milling. XRPD was used as the main technique to evaluate the milled samples. Ranitidine hydrochloride (RAN) and indomethacin (INDO) were the model drugs used in this study. It was found that upon milling, RAN form 1 converts to RAN form 2 via an amorphous phase. A faster amorphization rate was observed when the crystalline samples were cryo-milled. Amorphous ranitidine hydrochloride was characterized to have a glass transition (T[g]) range of 13 to 30 �C and a crystallization exotherm (T[c]) between 30 and 65 �C. Conversion was found to occur faster when the temperature of the solid powder was greater than the T[c]. Under various storage conditions, similarly, crystallization of the amorphous phase mainly led to RAN form 2. However, some form 1 and amorphous phase was also detected on the XRPD diffractograms. Using partial least squares regression, the amount of solid form components in the ternary RAN mixtures were successfully quantified. RAN form 2 did not convert to form 1 under any milling (including cryo-milling) or storage conditions used in this study. Overall, RAN form 2 was found to be the thermodynamically stable form and the two (RAN) polymorphs are likely to be a monotropic pair. In a co-milling study of INDO and RAN, the two crystalline drugs were successfully converted into a single amorphous phase after 60 min of co-milling in a cold room (4 �C). The T[g] range (26-44 �C) was also characterized for these mixtures. DRIFTS spectra of the co-milled amorphous samples indicated an interaction had occurred between the carboxylic acid carbonyl (HO-C=O) and benzonyl amide (NC=O) of the INDO molecule with the aci-nitro (C=NO₂) of RAN. Depending on the ratio of INDO to RAN, in general, the amorphous mixtures were stable at 4 �C after 30 days of storage. Crystallization was faster when the binary mixtures were stored at higher temperature or contained higher amounts of RAN in the mixture. Although XRPD and DRIFTS suggested an interaction between the two drugs, co-crystal formation was not observed between INDO and RAN. Ball milling can be used to produce amorphous drug. The rate and extent of amorphization is dependent on the milling conditions. A faster rate of amorphization was observed when the crystalline drugs were cryo-milled. Amorphous drug formation can be made either alone or in combination with another crystalline drug. Amorphization could offer a significant improvement on the dissolution profile and the bioavailability of the poorly water soluble drug - indomethacin. Furthermore, ball milling can also be used to produce a homogenous mix between solids. The �goodmix� effect can be used for seed-induced crystallization or, when the XRPD or Raman data were combined with partial least squares regression, to create a reliable calibration model for quantitative analysis.

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Garrett, Andrew. "The role of subgroups and sub-populations in drug development and drug regulation". Thesis, Open University, 2006. http://oro.open.ac.uk/54629/.

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This thesis addresses the role of subgroups and sub-populations in drug development and regulation and includes the critical appraisal of regulatory guidance. Chapter One introduces clinical trial methodology and describes the current regulatory environment. In Chapter Two, randomisation is reviewed in relation to unbiased estimation of treatment differences and the impact of data exclusion to form subsets is described. Simpson's paradox (SP) is considered in Chapter Three. Randomisation is shown to protect against SP, while a treatment by factor interaction is not required. Balance is redefined for the odds formulation leading to identical unconditional and conditional parameters. The chances of SP (and less extreme inconsistencies) occurring are quantified using simulation, with varying sample size. Chapter Four considers treatment by subgroup interactions. Suggestions regarding the magnitude of a clinically relevant interaction are presented while a simple Bayesian approach to evaluate interactions using margins for the interaction parameter is applied to published data. Chapter Five considers non-inferiority in relation to sub-populations and covariate adjustment for binary outcomes. It is shown that the Per Protocol population is not necessarily conservative and simulation is used to demonstrate the impact on the type I and II errors. Using simulations it is shown that an increase in the type I error occurs if an important covariate is excluded from the logistic model when testing for non-inferiority. Chapter Six is directed towards the sub-population of children. The impact of off-label treatment is discussed in relation to the ethics of placebo-controlled trials, together with the importance of randomisation in evaluating long-term safety. In Chapter Seven, a therapeutic area is selected to ilJustrate the challenges raised during the previous chapters and wording changes to current regulatory guidelines are proposed. The thesis closes with personal thoughts regarding the future potential for individualised treatment.

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Malm, Mikaela. "Drug Analysis : Bioanalytical Method Development and Validation". Doctoral thesis, Uppsala universitet, Analytisk kemi, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8547.

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This thesis describes bioanalytical methods for drug determination in biological matrixes, with drugs in focus used against diseases largely affecting low-income countries. Solid-phase extraction is used for sample cleanup, and processed samples are analyzed by liquid chromatography. Developed bioanalytical methods are validated according to international guidelines. Eflornithine (DFMO) is a chiral drug, used for treating human African trypanosomiasis. A bioanalytical method for determination of DFMO enantiomers in plasma is presented. The enantiomers are detected by evaporative light-scattering detection. The method has been applied to determination of D-DFMO and L-DFMO in rats, after intravenous and oral administration of racemic DFMO. It is concluded that DFMO exhibits enantioselective absorption, with the more potent enantiomer L-DFMO being less favored. Sulfadoxine (SD) and sulfamethoxazole (SM) are sulfa-drugs used for malaria and pneumonia respectively. Two methods are described for simultaneous determination of SD and SM in capillary blood sampled on filter paper. The former method allows direct injection of extracts from dried blood spots (DBS), while for the latter method solid-phase extraction is added. Pre-analytical factors contributing to measurement uncertainty is also discussed, and it is concluded that it is of high importance that homogeneity in type of sampling paper and sampling volume is assured. Piperaquine (PQ) is an antimalarial, increasingly used in artemisinin combination therapy. A method for determination of piperaquine in DBS is presented. By using a monolithic LC column, a very short LC analysis of two minutes per sample is achieved. A method for simultaneous determination of three antiretroviral drugs i.e. lamivudine (3TC), zidovudine (AZT) and nevirapine (NVP), in DBS samples is described. The method is applied to drug determination in two subjects after receiving standard antiretroviral treatment. Conclusion is that the method is suitable for determination of 3TC and NVP, and to some extent for AZT.

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Andrée, Bengt. "Positron emission tomography in serotonergic drug development /". Stockholm, 2001. http://diss.kib.ki.se/2001/91-628-4779-1/.

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Rahman, Nargis Jahan. "Incorporation of population pharmacokinetics into drug development". Thesis, Imperial College London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325239.

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Goddard, Phylis Maud. "Clinically predictive models for platinum drug development". Thesis, Institute of Cancer Research (University Of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.287475.

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Rajapakse, Thiaga Anuradha. "Biopharmaceutical drug development modelling and portfolio management". Thesis, University College London (University of London), 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.413689.

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Howe, Christopher D. (Christopher Dwight). "Financial model of the drug development process". Thesis, Massachusetts Institute of Technology, 1995. http://hdl.handle.net/1721.1/9832.

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Carroll, Kevin. "Statistical issues in oncologic clinical drug development". Thesis, University of East Anglia, 2013. https://ueaeprints.uea.ac.uk/47985/.

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Cai, Xiaoshu. "DEVELOPMENT OF COMPUTATIONAL APPROACH FOR DRUG DISCOVERY". Case Western Reserve University School of Graduate Studies / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=case1465403528.

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Senderoff, Richard I. "Development of fibrin-based drug delivery systems /". The Ohio State University, 1990. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487677267728699.

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Cash, Devin R. "DRUG AND VACCINE DEVELOPMENT FOR NEISSERIA GONORRHOEAEA". VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4093.

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Neisseria gonorrhoeae, the causative agent of the STI gonorrhea, is not preventable by vaccination and is rapidly developing resistance to antibiotics. One important strategy for gonococcal survival in the host is iron acquisition in the face of nutritional immunity. To overcome iron limitation, the gonococcus expresses TonB dependent transporters (TdTs), outer membrane proteins that facilitate nutrient acquisition. Of the TdTs, the transferrin (Tf), lactoferrin (Lf), and hemoglobin (Hb) receptors hijack iron directly from host proteins, and studies have already shown that the Tf receptor is essential for the initiation of human infection. Given that the TdTs are virulence factors, they are widely conserved across strains, and are not subject to antigenic variation, they are ideal targets for novel therapeutics and vaccine development. As such, studies exploring these proteins and their potential as vaccine candidates and antimicrobial targets are needed. In this study we report that loops of the Tf receptor protein TbpA are not strongly immunogenic, and the antibodies raised against them are incapable of inhibiting TbpA-Tf interactions on the gonococcal cell surface. We also report that the loop 3 helix motif of TbpA is a critical functional domain for Tf-binding and iron uptake; however, no single residue was identified that was essential for these functions. In addition, we report the development of a platform for the structure-function analysis of HpuA, a member of the poorly studied Hb receptor. We also present evidence that novel small molecules may be able to inhibit TbpA-Tf interaction, presenting the Tf receptor as a novel, species-specific antimicrobial target. Finally, we demonstrated that a novel drug, OSU-03012, has antimicrobial activity against the gonococcus through down-regulation of DnaK, a protein chaperone. These findings suggest that DnaK, a widely conserved protein, may be a universal target for antimicrobial development. These studies provide insight into the structure function relationship of TbpA, the drug potential of DnaK, and lay the framework for future investigations of the TdTs for use in a multi-antigen vaccine.

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Hulín, Michal. "A drug development from risk management perspective". Master's thesis, Vysoká škola ekonomická v Praze, 2011. http://www.nusl.cz/ntk/nusl-124943.

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The purpose of this diploma thesis is to understand financing of drug development from an enterprise risk management perspective as well as to critically assess the efficiency of the ISO framework and risk management techniques used for determining whether to fund drug development or not. The diploma thesis is divided into theoretical and practical part. The first part starts with perception and assessment of uncertainty and risk in the past. It describes how risk-averse individuals attempted to deal with uncertainty and different risk. This is followed by the evolution of traditional risk management into the fast developing enterprise risk management. The text further analyses commonly used risk management standards COSO ERM and ISO 31000:2009. However, the main focus is on the critical assessment of analytical tools which are frequently used for evaluating and assessing risks, especially financial ones, during drug development. The theoretical part is finished by a drug development process, whose phases are briefly described. The practical part was written in co-operation with AstraZeneca, a top-notch pharmaceutical company. The overview of its business is preceded by an explanation of current issues in the pharmaceutical industry. Furthermore, the risk analysis is conducted with respect to the ISO framework. Subsequently, selected risk assessment techniques are applied on the simplified financial model of two different drugs, which was created based on AstraZeneca's real data. These risk assessment tools are used in different phases of drug development so it could be seen clearly how the results are changing during a project. The outcomes of this risk analysis are compared with original plans used by AstraZeneca which were used for deciding whether to fund drug development or not.

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Tran, Anh. "Development of new drug leads for tuberculosis". Thesis, The University of Sydney, 2014. http://hdl.handle.net/2123/11637.

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Tuberculosis (TB), caused by infection with the bacterium Mycobacterium tuberculosis, has re-emerged as a global health risk with a significant proportion of new TB cases classified as multi-drug resistant (MDR) or extensively drug resistant (XDR). As such, there is a desperate need for the development of TB therapies which operate via novel modes of action. This thesis outlines the development of new drug leads for tuberculosis employing a target-based approach and by synthesis and derivatization of natural product scaffolds. Specifically, the first and second section of the thesis describes the target-based approach towards the development of inhibitors against enzymes in the shikimate and peptidoglycan biosynthetic pathways such as type II dehydroquinase (type II DHQase) and N-acetylglucosamine-1-phosphate (GlmU) uridyltransferase. These enzymes have been demonstrated to be essential for the survival and virulence of M. tuberculosis in vitro. The third section of the thesis describes the development of synthetic derivatives of sansanmycins, uridylpeptide antibiotics isolated from Streptomyces spp. SS. Inhibition of M. tuberculosis type II DHQase is the subject of chapter 3 of this thesis. Initial synthetic efforts were directed at the preparation of inhibitors possessing an anhydroquinate core which served as a mimic for the enol intermediate of the type II DHQase catalyzed reaction. A library of inhibitors with triazole and alkyne linkers designed to bridge the anhydroquinate core with various aryl and heteroaryl groups were synthesized from a common ene-yne intermediate employing Cu(I) azide-alkyne cycloaddition and palladium catalyzed Sonogashira cross-coupling. The majority of compounds exhibited potent inhibition of M. tuberculosis type II DHQase (Ki = 0.039-3.2 M). Despite the potent inhibition against M. tuberculosis type II DHQase, anhydroquinate-based compounds exhibited poor inhibition of M. tuberculosis (H37Rv) in vitro. The lack of antitubercular activity was mainly attributed to the hydrophilicity of the anhydroquinate core which makes it difficult for these compounds to traverse the waxy, hydrophobic M. tuberculosis cell wall. This problem was addressed by substituting this core with functionally simpler, more hydrophobic fragments. A fragment elaboration approach was subsequently employed to devise novel type II DHQase inhibitors. This fragment elaboration study led to the identification and development of catechol and acetonide-based compounds which exhibited low micromolar inhibition against M. tuberculosis type II DHQase (Ki = 5-86 μM) and markedly improved antitubercular activity relative to anhydroquinate-based inhibitors (MIC50 = 10-850 μM against the avirulent H37Ra strain of M. tuberculosis). Chapter 5 of this thesis outlines the successful development of a continuous enzyme kinetic assay for M. tuberculosis GlmU uridyltransferase. It also features the design of inhibitors based on the substrates and putative transition-state of the GlmU uridyltranferase reaction. Three classes of substrate-based inhibitors based on aminothiazole, sulfonamide and chromone scaffolds were synthesized along with transition-state mimics. Unfortunately, these compounds only demonstrated weak to moderate inhibition of M. tuberculosis GlmU uridyltransferase. This chapter also outlines the successful synthesis of the first inhibitors of M. tuberculosis GlmU uridylransferase based on an aminoquinazoline scaffold which exhibited micromolar inhibitory activity. The structure-activity relationships (SARs) elucidated from this series of compounds will aid the design of more potent compounds in the future. Chapter 6 of this thesis focuses on the development of a low-epimerization fragment condensation strategy to assemble analogues of sansanmycins with high optical purity. A total of nine sansanmycin analogues were synthesized and evaluated for in vitro growth inhibition of M. tuberculosis H37Rv. Most compounds exhibited excellent antitubercular activity with MIC50 values in the high nanomolar to low micromolar range (0.3-2.2 μM). Preliminary data indicated that these compounds demonstrated intracellular killing of M. tuberculosis in infected human THP-1 macrophages. The SARs elucidated for the first-generation sansanmycin analogues now form the foundation for the design and synthesis of more potent second-generation compounds. The activity of these compounds in macrophage killing assays holds promise for the in vivo evaluation of these analogues.

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39

Kanzi, Aquillah Mumo. "Falcipains as malarial drug targets". Thesis, Rhodes University, 2013. http://hdl.handle.net/10962/d1003842.

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Malaria is an infectious disease caused by parasites of the Plasmodium genus with mortality rates of more than a million annually, hence a major global public health concern. Plasmodium falciparum (P. falciparum) accounts for over 90% of malaria incidence. Increased resistance to antimalarial drugs by the Plasmodium parasite, coupled with the lack of an effective malaria vaccine necessitates the urgent need for new research avenues to develop novel and more potent antimalarial drugs. This study focused on falcipains, a group of P. falciparum cysteine proteases that belong to the clan CA and papain family C1, that have emerged as potential drug targets due to their involvement in a range of crucial functions in the P. falciparum life cycle. Recently, falcipain-2 has been validated as a drug target but little is known of its Plasmodium orthologs. Currently, there are several falcipain inhibitors that have been identified, most of which are peptide based but none has proceeded to drug development due to associated poor pharmacological profiles and susceptibility to degradation by host cysteine proteases. Non-peptides inhibitors have been shown to be more stable in vivo but limited information exists. In vivo studies on falcipain-2 and falcipain-3 inhibitors have also been complicated by varying outcomes, thus a good understanding of the structural variations of falcipain Plasmodium orthologs at the active site could go a long way to ease in vivo results interpretation and effective inhibitor design. In this study, we use bioinformatics approaches to perform comparative sequence and structural analysis and molecular docking to characterize protein-inhibitor interactions of falcipain homologs at the active site. Known FP-2 and FP-3 small molecule nonpeptide inhibitors were used to identify residue variations and their effect on inhibitor binding. This was done with the aim of screening a collection of selected non-peptide compounds of South African natural origin to identify possible new inhibitor leads. Natural compounds with high binding affinities across all Plasmodium orthologs were identified. These compounds were then used to search the ZINC database for similar compounds which could have better binding affinities across all selected falcipain homologs. Compounds with high binding affinities across all Plasmodium orthologs were found.

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40

Ramsden, Justine. "Development of a TSM biosensor for the determination of DNA-drug interactions : a novel method to assist drug development". Thesis, De Montfort University, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.271708.

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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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Schlipp, Katherine M. "Analytical method development a mathematical approach /". Electronic version (PDF), 2004. http://dl.uncw.edu/etd/2004/schlippk/katherinschlipp.pdf.

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Öhman, Daniel. "Bioanalytical development for application in therapeutic drug monitoring : focus on drugs used in psychiatry /". Linköping : Univ, 2003. http://www.bibl.liu.se/liupubl/disp/disp2003/med775s.pdf.

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Ghorpade, S. R. "Development of chemoenzymatic methods for the preparation of optically pure drugs and drug intermediates". Thesis(Ph.D.), CSIR-National Chemical Laboratory, Pune, 2001. http://dspace.ncl.res.in:8080/xmlui/handle/20.500.12252/2305.

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McCallum, Emma Clare. "Adaptive phase II clinical trial design using nonlinear dose-response models". Thesis, University of Cambridge, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.709013.

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Silal, Sheetal Prakash. "A simulation model of antimalarial drug resistance". Master's thesis, University of Cape Town, 2009. http://hdl.handle.net/11427/9003.

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Includes bibliographical references (leaves 132-137).
Malaria ranks among the world's most important tropical parasitic diseases with world prevalence figures between 350 and 550 million clinical cases per annum. [WHO, 2008a] 'Treatment and prevention of malaria places a considerable burden on struggling economies where the disease is rampant. Research in malaria does not stop as the change in response to antimalarial drug treatment requires the development of new drugs and innovation in the use of old drugs. This thesis focused on building a model of the spread of resistance to Sulfadoxine/Pyrimethamine (SP) in a setting where both SP and SP in artemisinin-based combination therapy (ACT) are the first line therapies for malaria. The model itself is suitable to any low transmission setting where antimalarial drug resistance exists but the country of choice in this modeling exercise was Mozambique. The model was calibrated using parameters specific to the malaria situation in Mozambique. This model was intended to be used to aid decision making in countries where antimalarial drug resistance exists to help prevent resistance spreading to such an extent that drugs lose their usefulness in curing malaria. The modeling technique of choice was differential equation modeling; a simulation technique that falls under the System Dynamics banner in the Operations Research armamentarium. It is a technique that allowed the modeling of stocks and flows that represent different stages or groupings in the disease process and the rate of movement between these stages respectively. The base model that was built allowed infected individuals to become infectious, to be treated with SP or ACT and to be sensitive to or fail treatment. Individuals were allowed a period of temporary immunity where they would not be reinfected until the residual SP had been eliminated from their bloodstream. The base model was then further developed to include the pharmacokinetic properties of SP where individuals were allowed to be reinfected with certain strains of infection given the level of residual drug in their bloodstream after their current infection had been cleared. The models used in this thesis were built with idea of expanding on previous models and using available data to improve parameter estimates. The model at its core is similar to the resistance model used in Koella and Antia [2003] where differential equation modeling was used to monitor a population as it became infected with a sensitive or resistant infection and then University of Cape Town recovered. The inclusion in the model of the PK component was derived from Prudhomme-O'Meara et al. [2006] where individuals could be reinfected depending on the residual drug in their bloodstream. Rather than modeling simply sensitive and resistant infections, mutations categories were used as was the case in Watkins et al. [2005] population genetics model. The use of mutation categories allowed one to use parameters specific to these categories rather than the sensitive/resistant stratification and this is particularly relevant in Mozambique where all mutation categories still exhibit some degree of sensitivity to treatment i.e. total resistance has not yet developed for any particular mutation category. The last adaptation of the model was to use gametocyte information directly to determine human infectiousness rather than through using a gametocyte switching rate (constant multiplier used to convert parasite density to gametocyte density) as was done in Pongtavompinyo [2006]. The models developed in this thesis found that the existing vector control and drug policy in Mozambique had the major effect of decreasing total prevalence of malaria by approximately 70% in the 11 year period. The distribution of Res3 (presence of DHFR triple) and Res5 (presence of DHFR triple and DHPS double) infections changed over the 11 year period with Res3 infections initially increasing and then decreasing while Res5 infections started low and increased to overtake Res3 infections. The timing of the change in this composition of infection corresponds with the introduction of ACT and thus it appears that the use of ACT prompted the increased prevalence of quintuple parasites over DHFR triple and sensitive parasites. The total number of failures decreased substantially after the introduction of ACT to 17% of its previous level. The results of the base model corresponded with the observed data from the SEACAT study in terms of the magnitude and the trends of the impact of the change to ACT policy, but underestimated the impact of the vector control strategies compared to rapid effect noted in Sharp et al. [2007]. The Scenario testing of the base model showed that vector control is an effective strategy to reduce prevalence and that it is sensitive to the time at which the control is started as it decreased prevalence very gradually. The Scenario testing of the base model also showed that the introduction of ACT in Mozambique had a greater impact on reducing prevalence and that the start time of the ACT strategy did not decrease the effect on prevalence though earlier start times decreased the total number of resistance cases. The ratio of Res5 to Res3 infections increased faster when ACT was the treatment policy than when SP was the policy. Thus higher values of this ratio are associated with ACT being the treatment strategy in place. Thus differential equation modeling is an effective modeling tool to capture the spread of disease and to test the effects of policy interventions as it allows one to assess these effects on populations and averages out individual-level intricacies to better inform policy decisions.

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Cereto, Massagué Adrià. "Development of tools for in silico drug discovery". Doctoral thesis, Universitat Rovira i Virgili, 2017. http://hdl.handle.net/10803/454678.

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El cribratge virtual és un mètode quimioinformàtic que consisteix en cribrar molècules bioactives de grans bases de dades de molècules petites. Això permet als investigadors d’estalviar-se el cost de provar experimentalment cents o milers de compostos candidats, reduïnt-ne el nombre fins a quantitats manejables. Per a la validació dels mètodes de cribratge virtual calen biblioteques de molècules cimbell. El programari DecoyFinder fou desenvolupat com a aplicació gràfica de fàcil ús per a la construcció de biblioteques de molècules cimbell, i fou posteriorment ampliat amb les troballes de recerca posterior sobre la construcció i rendiment de biblioteques de molècules cimbell. El Protein Data Bank (PDB) és molt útil perquè proporciona estructures tridimensionals per a complexos proteïna-lligand, i per tant, informació sobre com interactuen. Pels mètodes de cribratge virtual que en depenen, n’és extremadament important la seva fiabilitat. El VHELIBS fou desenvolupat com a eina per a inspeccionar i identificar, fàcilment i intuitiva, les estructures fiables del PDB, basant-se en com de bo n’és l’encaix amb els seus corresponents mapes de densitat electrònica. Mentre que el cribratge virtual prova de trobar noves molècules bioactives per determinades dianes, l’enfoc invers també s’empra: arran d’una molècula, cercar-ne dianes amb activitat biològica no documentada. Aquest cribratge invers és conegut en anglès com a “in silico target fishing”, o pesca de dianes “in silico”, i és especialment útil a l’àmbit de la reutilització de fàrmacs En començar aquesta tesi, no hi havia cap plataforma de “target fishing” de lliure accés, i tot i que durant els anys se n’han desenvolupat algunes, en tots els casos la seva predicció de bioactivitat és qualitativa. Per això es desenvolupà una plataforma pròpia de “target fishing” de lliure accés, amb la implementació d’un nou mètode que proporciona la primera predicció quantitativa de bioactivitat per aquest tipus de plataforma.
El cribado virtual es un método quimioinformático que consiste en la criba de moléculas bioactivas de grandes bases de datos de moléculas pequeñas. Esto permite a los investigadores ahorrarse el coste de probar experimentalmente cientos o miles de compuestos candidatos, reduciéndolos hasta cantidades manejables. Para la validación de los métodos de cribado virtual hacen falta bibliotecas de moléculas señuelo. El software DecoyFinder fue desarrollado como aplicación gráfica de fácil uso para la construcción de bibliotecas de moléculas señuelo, y fue posteriormente ampliado con los hallazgos de investigación posterior sobre la construcción i rendimiento de bibliotecas de moléculas señuelo. El Protein Data Bank (PDB) es muy útil porque proporciona estructuras tridimensionales para complejos proteina-ligando, y por tanto, información sobre como interactúan. Para los métodos de cribado virtual que dependen de ellas, es extremadamente importante su fiabilidad. VHELIBS fue desarrollado como herramienta para inspeccionar e identificar, fácil e intuitivamente, las estructuras fiables del PDB, basándose en como de bueno es su encaje con sus correspondientes mapas de densidad electrónica. Mientras que el cribado virtual intenta encontrar nuevas moléculas bioactivas para determinadas dianas, el enfoque inverso también se utiliza: a partir de una molécula, buscar dianas donde presente actividad biológica no documentada. Este cribado inverso es conocido en inglés como “in silico target fishing”, o pesca de dianas “in silico”, y es especialmente útil en el ámbito de la reutilización de fármacos. Al comenzar esta tesis, no había ninguna plataforma de “target fishing” de libre acceso, y aunque durante los años se han desarrollado algunas, en todos los casos su predicción de bioactividad es cualitativa. Por eso se desarrolló una plataforma propia de “target fishing” de libre acceso, con la implementación de un nuevo método que proporciona la primera predicción cuantitativa de bioactividad para este tipo de plataforma.
Virtual screening is a cheminformatics method that consists of screening large small-molecule databases for bioactive molecules. This enables the researcher to avoid the cost of experimentally testing hundreds or thousands of compounds by reducing the number of candidate molecules to be tested to manageable numbers. For their validation, virtual screening approaches need decoy molecule libraries. DecoyFinder was developed as an easy to use graphical application for decoy library building, and later updated after some research into decoy library building and their performance when used for 2D similarity approaches. The Protein Data Bank (PDB) is very useful because it provides 3D structures for protein-ligand complexes and, therefore, information on how certain ligands bind and interact with their targets. For virtual screening apporaches relying on these structures, it is of the utmost importance that the data available on the PDB for the ligand and its binding site are reliable. VHELIBS was developed as a tool to easily and intuitively inspect and identify reliable PDB structures based on the goodness of fitting between ligands and binding sites and their corresponding electron density map. While virtual screening aims to find new bioactive molecules for certain targets, the opposite approach is also used: starting from a given molecule, to search for a biological target for which it presents previously undocumented bioactivity. This reverse screening is known as in silico or computational target fishing or reverse pharmacognosy, and it is specially useful for drug repurposing or repositioning. When this thesis was started, there were no freely available target fishing platforms, but some have been developed during the years. However, they are qualitative in the nature of their activity prediction, and thus we set out to develop a freely accessible target fishing web service implementing a novel method which provides the first quantitative activity prediction: Anglerfish.

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Zong, Jingyi. "The development of anti-cancer drug delivery systems". Thesis, Durham University, 2016. http://etheses.dur.ac.uk/11927/.

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Cancer is undoubtedly one of the main threats to global human health and as a result, despite significant advances in the field, new and improved cancer treatments are still in great need. Although chemotherapy (in combination with other therapies) is widely used to suppress the growth of tumours, many of the current anti-cancer drugs suffer from poor selectivity and consequently severe toxicity. In order to conquer these limitations, targeted drug delivery systems have been designed and studied with the primary aim of improving the accuracy of transporting anti-cancer drugs into cancer cells and tissue areas. The overall aim of the work presented in this thesis is to design new anti-cancer drug delivery systems using three different strategies. In Chapter 2, intelligent stimulus-responsive short elastin-like peptides (ELPs) and elastin-based side chain polymers (ESPs) were synthesised. The conformation and aggregation properties of these ELPs and ESPs were studied in different aqueous buffers (varying pH also) using ultraviolet-visible (UV-Vis) spectroscopy and circular dichroism (CD). Of the ELPs investigated, peptide 10 (N-acetylated VPGVG) was found to have the lowest transition temperature at pH 7 (i.e. 45oC). Amongst all the ESPs, PF100-GABA(VPGVG) (29) was proven to have the lowest transition temperature (47oC) which was most likely due to the fact that it had the highest molecular weight. In Chapter 3, gold nanoparticles (GNPs) were synthesised and functionalised with biomolecules including elastin-like peptides (ELPs), elastin-based side chain polymers (ESPs) and the pro-apoptotic peptide D-(KLAKLAK)2 (KLA). The hybrids materials, ELP-GNPs and ESP-GNPs were characterized by UV-Vis, CD and transmission electron microscopy (TEM). The hybrids showed the same temperature sensitive properties as the free ELPs and ESPs previously studied, confirming the successful functionalization of GNPs. The KLA-GNPs were found to have increased anti-cancer activity against HeLa cells compared to the free KLA. In Chapter 4, the pro-apoptotic KLA peptide was conjugated to a series of cell penetrating peptoids (CPPos) to prepare peptoid-peptide hybrids (CPPos-KLA). The anti-cancer, antimicrobial and cell penetrating properties of these peptoid-peptide hybrids were investigated. The results demonstrated an increasing trend in anti-cancer ability of CPPos-KLA hybrids (compared to free KLA) and KLA-CPPo6 (57) gave the lowest IC50 value (ca.8 μM) against HeLa cells.

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Acoca, Stephane. "In silico methods in drug discovery and development". Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=110376.

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Computational drug design methods have become increasingly invaluable in the drug discovery and development process. Throughout this thesis will be described the development and application of methods that are used at every stage of the drug discovery and development pipeline. In Chapter 2 will take a look at the use computational methods towards the understanding and development of two novel Bcl-2 inhibitors, Obatoclax and ABT-737, being developed for the treatment of Cancer. The study proposes certain mechanisms through which ABT-737 displays selectivity towards certain targets within the Bcl-2 family. Additionally, we propose a binding mode for Obatoclax which is in accordance with experimental data. The following Chapter addresses the use of virtual screening for the identification of novel lead compounds. Trypanosoma brucei RNA Editing Ligase 1 was chosen as the target for the development of treatments against Trypanosoma infections and C35, a potent novel inhibitor of the enzyme, was identified. Furthermore, our research shows that the action of C35 extends to inhibition of several critical enzyme activities required for the RNA editing process as well as compromising the integrity of the multiprotein complex which carries it out. The following Chapter takes a look at the use of mass spectrometry data in order to expedite discovery of bioactive compounds in natural products. We developed an algorithm which analyses MS/MS data in order to derive the Molecular Formula of the compound. The novel algorithm obtained a 95% success rate on a test set of 91 compounds. The last Chapter of the thesis explores the use of molecular dynamics to generate a conformational ensemble of targets for virtual screening. Conformational ensembles were generated for a target test set taken from the Directory for Useful Decoys. The results showed that molecular dynamics-based conformational ensembles provided remarkable improvements on 2 of the targets tested due to the enhanced capacity to properly dock compounds in otherwise restricted structures. The last Chapter of the thesis is a general discussion on the work of the thesis and a proposal on how all can be integrated within the drug discovery and development pipeline.
Les méthodes the modélisation sont devenues un outil inestimable dans le processus de découverte et de développement de nouveaux médicaments. Au cours de cette thèse va être décrit le développement et l'application de méthodes utilisés à chaque stage de la découverte et du développement de produits pharmaceutiques. Le Chapitre 2 est un aperçu sur l'utilisation de méthodes computationnelles vers le développement de deux nouveaux inhibiteurs des protéines Bcl-2, Obatoclax et ABT-737, en développement pour le traitement du Cancer. L'étude propose certains mécanismes d'ABT-737 qui expliquent ca sélectivité envers les membres de la famille Bcl-2. De plus, nous proposons un mécanisme d'attachement pour Obatoclax qui conforme aux données expérimentales. Le Chapitre suivant adresse l'utilisation du dépistage virtuel pour l'identification de nouvelles molécules mère. La Ligase de l'Edition d'ARN du Trypanosoma brucei a été choisie comme cible pour le développement de traitements contre des infections dû au Trypanosome et C35 a été identifié comme nouvel inhibiteur de l'enzyme. En outre, notre recherche démontre que l'action de C35 s'étends a l'inhibition de plusieurs enzymes nécessaires pour le mécanisme d'édition de l'ARN en plus de compromettre l'intégrité du complexe multi-protéinique qui l'effectue. Le Chapitre suivant prends regard a l'utilisation de donnes dérivant de la spectrométrie de masse pour but d'accélérer la découverte de molécules bioactives venant de sources naturelles. Nous avons développé un algorithme qui analyse les données MS/MS pour but de dériver la formule moléculaire du composé. Le nouvel algorithme a obtenu un taux de succès s'élevant à 95% sur un ensemble test de 91 molécules. Le dernier Chapitre de la thèse explore l'utilisation de simulations de dynamique moléculaire pour générer en ensemble conformationel de protéines cible pour son utilisation dans le dépistage virtuel. Les ensembles conformationel ont étés généré pour une série test obtenu d'un répertoire attitré 'Directory for Useful Decoys'. Les résultats démontrent que les ensembles conformationel dérivés de la dynamique moléculaire ont apporté des améliorations remarquables sur deux des cibles testées dû à une capacité accrue de placement approprié des molécules dans un site qui est autrement très restreint. Le dernier Chapitre de cette thèse est une discussion générale sur le travail accomplie et une proposition sur la manière dont tous les éléments sont intégrer dans un protocole de découverte et de développement de produits pharmaceutiques.

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Saovapakhiran, Angkana. "Development of novel dendrimer carriers for drug delivery". Thesis, University of Reading, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.492737.

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Polyamidoamine (PAMAM) dendrimers represent a novel type of polymer with numerous pharmaceutical applications and have been en investigated as transcellular carriers. However, the mechanisms of cellular uptake and intracellular processing of dendrimers are not fully understood. In this study the mechanism of cellular uptake of PAMAM dendrimer and surface-modified PAMAM dendrimers was investigated in order to optimise dendrimers as potential drug carriers.

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