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Shi, Yun, and 施昀. "Escalation with overdose control for phase I drug-combination trials." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hub.hku.hk/bib/B49799733.
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The escalation with overdose control (EWOC) method is a popular modelbased dose finding design for phase I clinical trials. Dose finding for combined drugs has grown rapidly in oncology drug development. A two-dimensional EWOC design is proposed for dose finding with two agents in combination based on a four-parameter logistic regression model. During trial conduct, the posterior distribution of the maximum tolerated dose (MTD) combination is updated continuously in order to find the appropriate dose combination for each cohort of patients. The probability that the next dose combination exceeds the MTD combination can be controlled by a feasibility bound, which is based on a prespecified quantile for the MTD distribution such as to reduce the possibility of over-dosing. Dose escalation, de-escalation or staying at the same doses is determined by searching the MTD combination along rows and columns in a two-drug combination matrix. Simulation studies are conducted to examine the performance of the design under various practical scenarios, and illustrate it with a trial example.<br>published_or_final_version<br>Statistics and Actuarial Science<br>Master<br>Master of Philosophy
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Almoyad, Muhammad. "Synergism from combination of targeted therapy and phytochemicals in colorectal cancer." Thesis, The University of Sydney, 2018. http://hdl.handle.net/2123/18161.
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Colorectal cancer is the second most common cancer in women and third in men, accounting for 9.7 % of all cancers incidence. Oxaliplatin is a platinum-based anticancer drug used typically in combination with folinic acid and 5-fluorouracil for treatment against colorectal cancer. However, numerous side effects such as nausea and vomiting, GI toxicity, anaemia, immunodeficiency, ototoxicity, nephrotoxicity, and neurotoxicity are associated with its use. These can be decreased by lowering dose of oxaliplatin. Phytochemicals that can act as antioxidants have been used by people in treatment against cancer throughout human history because of their low toxicity and the ease in availability. Besides providing protection against cancer, they can also kill cancer cells. Studies show that chemopreventive agents would boost activity of anticancer drugs and thus improve treatment outcome. In this study, resveratrol, thymoquinone, capsaicin and quercetin were applied to four human colorectal cancer cell lines HT-29, Caco-2, Lim-1215 and Lim-2405 in combination with platinum drugs cisplatin and oxaliplatin using three sequences of administration (0/0 h, 0/4 h and 4/0 h). Activity of compounds alone and in combination were determined using MTT reduction assay. Combination index was used as a measure of combined drug action. Studies on cellular accumulation, platinumDNA binding, DNA damage and proteomics were carried out to obtain mechanistic insights. In HT-29 cell line all sequences of administration produced antagonism at lower concentration (ED50). In Caco-2 cell line, bolus combination of cisplatin with resveratrol was found to produce moderate synergistic effect at all concentrations. In Lim-2405 cell line, combination of cisplatin with quercetin was found to produce most synergistic outcome. As applied to oxaliplatin, its combination with quercetin was found to produce most synergistic outcomes in Caco-2 cell line. Combination of oxaliplatin and capsaicin was most synergistic in Lim-2405 cell line. Results on PtDNA binding showed that synergistic effect was associated with higher platinumDNA binding. In proteomics study, 16 proteins belonging to different functional groupings were found to undergo changes in expression as a result of treatment with synergistic combinations.
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Al, Onazi Fahad Nasser. "Platinum drugs given in combination with phytochemicals to enhance platinum action." Thesis, The University of Sydney, 2017. http://hdl.handle.net/2123/18971.
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This study focused on the sequenced combinations of platinum drugs cisplatin and oxaliplatin and four phytochemicals celastrol, guggulsterone, garcinol and ellagic acid administered to human ovarian lines A2780, A2780cisR and A2780ZD0473R. Among the phytochemicals, celastrol is most active having comparable activity against all the three ovarian tumour models. As applied to binary combinations of platinum drugs and the phytochemicals, it was found that generally synergism was greater at higher concentrations (ED75 and ED90) of drugs than at lower concentrations (ED50) in all three cell lines. Often 0/0 h and 0/4 h sequences of administration were found to be more synergistic, giving support to the idea that pre-treatment or concurrent with the phytochemicals have served to activate the cancer cells towards assault by the platinum drugs. The reduced accumulation of platinum in the cisplatin resistant cell line A2780cisR as compared to the cisplatin sensitive cell line A2780, gives support to the concept that the reduced platinum accumulation is the principal mechanism by which the cisplatin resistant cell line A2780cisR cell line resist the platinum drugs action. The absence of any visible DNA band after interaction of A2780 cells with ellagic acid indicates total DNA damage so that the phytochemical is most damaging to DNA in A2780 cells. The results of the present study showed the levels of reduced form of glutathione (GSH) in the resistant cell line A2780cisR were higher than the parent cell line A2780, irrespective of whether the cells were treated with a single agent (cisplatin, oxaliplatin, or ellagic acid) or in combination, giving support to the idea that the higher levels of glutathione serve to be one of the central mechanisms of cisplatin resistance in ovarian cancer cells.
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Bali, Hana. "Synergism from combination of platinum drugs and selected phytochemicals in colorectal cancer." Thesis, The University of Sydney, 2018. http://hdl.handle.net/2123/18798.
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Colorectal cancer is the second most leading cause of death among all reported cancer mortality. Chemotherapy is the treatment of choice to treat metastasized colorectal cancer patients. Combined administration of drugs having different mechanism of actions has been demonstrated better efficacy than conventional monotherapy. Epidemiological data suggests that consumption of phytochemicals has a great impact in prevention and treatment of colorectal cancer. In this study four phytochemicals including curcumin, colchicine, EGCG and taxol were combined with cisplatin and oxaliplatin in a binary mode at three different concentrations and sequence of administrations against four different colorectal cancer cell lines (HT-29, CACO-2, LIM-1215 and LIM-2405). When oxaliplatin is combined with curcumin or EGCG, the cytotoxic outcome is more synergistically effective than the combination of cisplatin with either phytochemicals in a binary combination. However, cisplatin in combination with colchicine showed greater synergism than that of oxaliplatin with colchicine. Observed synergisms of the combinations were found to be correlated with platinumDNA binding and cellular accumulations of platinum. DNA damage study indicated that antagonistic combinations were less damaging towards DNA. Proteomic study revealed eleven proteins which displayed significant changes in expression following different drug treatments which were: NPM, ACTB, TBB5, HSP7C, K2CB, GSTP1, GRP78, PSB6, COF1, IDHC and K1C18. Among these proteins NPM and ACTB was considered as antiapoptotic whereas IDHC and K1C18 believed to be proapoptotic.
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Yang, Jianning. "Mechanism-Based Computational Models to Study Pharmacological Actions of Anticancer Drugs." The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1249622434.
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Siau, Hong. "The effects of antifungal drugs in combination on the growth of Candida species." Thesis, University of Cambridge, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.359415.
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Kaelen, Mendel. "The psychological and human brain effects of music in combination with psychedelic drugs." Thesis, Imperial College London, 2017. http://hdl.handle.net/10044/1/55900.
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This research investigated how psychedelics and music work together in the brain and modulate subjective experience. Chapter 1 highlighted the prominent role of music in psychedelic therapy in the 1950s and 1960s, and how music continues to be used in modern psychotherapeutic trials with psychedelics. Although ‘psychedelic therapy’ shows promising findings for mental health care, little is known empirically about the therapeutic functions of music. The primary objective of this thesis was to address this knowledge gap, via studying the effects of psychedelics and music on human brain function in healthy volunteers, and via studying the subjective experience of music, both in healthy volunteers and in patients undergoing psychedelic therapy. Study 1 (Chapter 3) demonstrated intensified music-evoked emotions under the classic psychedelic LSD, including emotions of ‘wonder’ and ‘transcendence’. In subsequent work (study 2, Chapter 4), increased activation in the inferior frontal gyrus and the precuneus to the timbre features in the music, was associated with increased music-evoked emotions of wonder. Study 3 (Chapter 5) demonstrated that LSD and music interact to enhance information flow from the parahippocampus to the visual cortex, and that this effect correlated with increased complex mental imagery and autobiographical memories. Study 4 (Chapter 6), showed that music has a substantial influence on the therapeutic experience with psilocybin in patients with depression, and the quality of the music-experience predicted peak experiences and insightfulness during sessions, and reductions in depression after sessions. These findings support the hypothesis that the music-experience is intensified under psychedelics, and the widely-held view that this effect may be therapeutically significant. Possible brain mechanisms and therapeutic mechanisms are discussed in Chapter 7, but further research is warranted to better understand these mechanisms, and to learn how music can be best used in psychedelic therapy.
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Cronin-Fine, Drew. "Pricing and reimbursement challenges for fixed dose combination cardiovascular drugs and intravenous oncologies." Thesis, Massachusetts Institute of Technology, 2012. http://hdl.handle.net/1721.1/72918.
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Thesis (S.M.)--Harvard-MIT Program in Health Sciences and Technology, 2012.<br>Cataloged from PDF version of thesis.<br>Includes bibliographical references (p. 63-67).<br>Over the past ten years there has been increasing public concern regarding the rising costs of pharmaceuticals. Drug expenditure is the fastest growing sector of healthcare costs in the United States. The structure of the U.S. healthcare system allows pharmaceutical companies to freely price their drugs. Then payers decide whether and how to cover these drugs. Payers have at their disposal several utilization management tools, such as tiering and prior authorizations, to steer their members to less costly drugs. However, the ability of payers to implement these tools varies significantly depending on whether the drug is covered under the pharmaceutical benefit / Medicare Part D provisions of healthcare plans or the medical benefit / Medicare Part B provisions. Drugs covered under the pharmaceutical benefit / Part D are distributed via retail pharmacies and, in general, are oral pills. Drugs covered under the medical benefit / Part B are physician administered drugs and, in general, are injectables or intravenous drugs. As pharmaceutical companies increasingly price their drugs at higher and higher levels, payers must take a drug's pricing into account when determining how to cover these drugs. This thesis assesses the role pricing plays in how a drug is covered. Two different classes of drugs were chosen to examine this topic: fixed dose combination (FDC) cardiovascular drugs and intravenous oncologies. FDC cardiovascular drugs were chosen because they are covered under the pharmacy benefit / Part D and are considered to have questionable efficacious value over their individual drug components. Intravenous oncologies were chosen because they are covered under the medical benefit / Part B and represent a highly politicized therapy area. These two therapy areas are illustrative of strongly contrasting classes of drugs. Literature review and public sources were used to obtain prices for the select cardiovascular FDCs and oncologies. Medicare's Formulary Finder was used to obtain the coverage level for the cardiovascular FDCs. This preliminary information showed that the most expensive of the select FDCs, Caduet, has the worst coverage. The literature review suggested that Provenge and Avastin, the most expensive of the select oncologies, had difficulty obtaining coverage. To confirm these results, interviews were conducted with a variety of payers. These interviews focused on what factors went into the coverage decision-making process for cardiovascular FDCs and intravenous oncologies. Interviews were also conducted with an oncologic distributor to determine distributors' impact on price. We hypothesized that price was the driving reason for Caduet's, Provenge's, and Avastin's relatively poor coverage. However, our hypothesis was not entirely confirmed. Payers confirmed that price and contracting were the driving factors for Caduet's relatively poor coverage, but they indicated that the situation was not as simple for the intravenous oncologies. Although price does play a small role in the coverage decision-making process for intravenous oncologies, other factors such as public policies and the unmet need in the therapy area drive coverage decisions more than price. Additionally, payers indicated that they lack the ability to steer members to less costly intravenous oncologies due to the drug acquisition and reimbursement structure of the medical benefit. Consequently, payers are beginning to utilize new techniques such as specialty pharmacies to help control utilization of these products. Also, other organizations such as certain oncologic distributors are attempting to implement cost-effective guidelines for intravenous oncologies. Our results have significant implications for what pharmaceutical companies should be considering when pricing their drugs, and highlight the pricing and coverage issues in the current healthcare system's structure that payers and other organizations are facing.<br>by Drew Cronin-Fine.<br>S.M.
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McLeese, Michelle Frances. "Increases in Drug and Alcohol Problems: A Combination of Job and Home Stressors?" Thesis, Virginia Tech, 2005. http://hdl.handle.net/10919/30846.
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Using data from the National Comorbidity Survey (NCS) from the Fall of 1990 to the Spring of 1992 among respondents between the ages of 15 and 54 in 48 of the contiguous United States, this paper hypothesized an increase in serious drug problems and serious alcohol problems when a combination approach was used regarding home and work stressors. Results indicate support for the hypotheses that the combination of home and work stressors leads to an increase in both serious drug and alcohol problems (each measured separately). These findings are important especially since they suggest that stressors from home affecting work are significant and positively related to problems with both alcohol and drugs and stressors from work affecting home are not. In addition to demographic controls and stress scales of work and home, the model takes into account other possible explanations. These include past traumatic or recent life events that are considered high in stress, the family background of the parents of the respondents with regard to past psychiatric disorders, and the comorbidity of the respondents themselves. Results imply that stressors from home affecting work are significant and matter more than work stressors affecting home in every model. This research improves upon previous research by both exploring the inter-relationship between home and work stress and controlling for alternative explanations. Although more research needs to be carried out in the area of â home stressors,â these results suggest previous conflicting findings within the work stress literature may be due in part to too narrow of a focus on stressors at the workplace or related to the job environment separate from home stressors.<br>Master of Science
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Soble, Michelle Joy 1961. "THE EFFECTS OF GLUTATHIONE DEPLETION BY L-BUTHIONINE-(S,R) SULFOXIMINE ON THE ANTITUMOR EFFICACY OF MODEL SULFHYDRYL-DEPENDENT ANTICANCER AGENTS (BSO)." Thesis, The University of Arizona, 1986. http://hdl.handle.net/10150/276859.
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Luu, Yao, Jim Thigpen, and Stacy D. Brown. "Stability of Sildenafil in Combination with Heparin and Dopamine." Digital Commons @ East Tennessee State University, 2017. https://doi.org/10.2146/ajhp150853.
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Purpose:The stability of sildenafil in combination with heparin and dopamine was evaluated.
Methods:A stability-indicating high-performance liquid chromatography method with ultraviolet detection was developed for sildenafil citrate and validated. The method was applied to the investigation of sildenafil alone, sildenafil with heparin, sildenafil with dopamine, and sildenafil with heparin and with dopamine, all in 5% dextrose injection at room temperature and under refrigeration for 30 days. Samples of 100 μL were pulled from each storage bottle on each sampling day, diluted in mobile phase, and assayed in duplicate. Samples were tested on days 0, 1, 2, 3, 4, 5, 7, 9, 12, 14, 21, and 30. Each preparation was visually inspected for precipitation and color change. The percent recovery in each study sample was determined by comparing the peak area of sildenafil in the sample with the peak area of sildenafil from a freshly prepared 100-μg/mL standard in mobile phase.
Results:The sildenafil alone, sildenafil with heparin, and sildenafil with dopamine remained within 90–110% of the expected sildenafil potency for at least 30 days at both temperatures. The preparation of sildenafil with both heparin and dopamine fell below 90% potency after 3 days at room temperature and 21 days in the refrigerator.
Conclusion:Sildenafil prepared in 5% dextrose injection alone, with heparin, and with dopamine retained over 90% potency after 30 days of storage at room temperature and under refrigeration. Sildenafil prepared with both heparin and dopamine had a potency of
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Wang, Jie Stamey James D. "Sample size determination for Emax model, equivalence / non-inferiority test and drug combination in fixed dose trials." Waco, Tex. : Baylor University, 2008. http://hdl.handle.net/2104/5182.
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Almeida, Neto Abílio César de. "Training community pharmacists in cognitive-behavioural intervention strategies for optimising the monitoring of non-prescription combination analgesic products." Connect to full text, 2000. http://hdl.handle.net/2123/833.
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Thesis (Ph. D.)--University of Sydney, 2000.<br>Includes tables. Title from title screen (viewed Apr. 23, 2008). Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the Dept. of Psychology, Faculty of Science. Includes bibliography. Also available in print form.
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Bach, Nielsen Anders. "Use of the combination of prodrug design and salt optimization - a strategy to enchance aqueous solubility of drugs /." Cph. : Department of Pharmaceutics, the Danish university of Pharmaceutical Sciences, 2004. http://www.dfh.dk/phd/defences/AndersBachNielsen.htm.
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Kim, Sung Woo. "Combining Noxa-Inducing Drugs with ABT-263 to Efficiently Increase Cell Death in Head and Neck Squamous Cell Carcinoma (HNSCC)." VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/4847.
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Head and neck cancer is the sixth leading cancer worldwide. Head and neck squamous cell carcinoma (HNSCC) accounts for more than 90% of incident cases. Despite intense, multimodality treatment regimens for HNSCC including surgery, chemotherapy, and radiation, little progress has been made over the past 30 years in improving overall survival rates. Tumor cell death induced by both conventional and targeted chemotherapy is often mediated by the BCL-2 family-dependent mitochondrial apoptotic pathway. However, initiators of this apoptotic pathway, such as p53, are more than 50% of the time mutated or deleted in HNSCC rendering the disease refractory to treatment. To counter such resistance, direct therapeutic targeting of the BCL-2 family is conceptually appealing. For this purpose, we use three clinically-available drugs: cisplatin, fenretinide, and ABT-263 (navitoclax). Both cisplatin and fenretinide are known to induce a BH3-only pro-apoptotic protein, Noxa, which binds to and inactivates multi-domain anti-apoptotic protein MCL-1 and release from its interaction with multi-domain pro-apoptotic protein BAK, followed by the phosphorylation via CDK2 for the proteasome-mediated degradation. Activated BAK can now go through conformational change for the oligomerization at the outer membrane of the mitochondria to release cytochrome c into the cytosol and induce caspase-dependent apoptotic cell death. ABT-263 directly binds to multi-domain anti-apoptotic proteins, such as BCL-2 and BCL-XL, to inhibit their activity and leads to the activation of multi-domain pro-apoptotic protein BAX to induce apoptosis.
We hypothesize that combining the Noxa-inducing drugs (cisplatin or fenretinide) along with ABT-263 can efficiently induce BAX and BAK activation and significantly increase cell death in HNSCC cells by simultaneously inhibiting the activity of MCL-1, BCL-2, and BCL-XL. Combination-induced treatments in four cell lines (HN8, HN30, HN31, and UMSCC1) tested led to significant increase in apoptotic cell death. Cisplatin and ABT-263 combined treatment is inducing the expression of Noxa and leading to increase in apoptosis in HN30, HN31, UMSCC1, but not HN8. Similarly, fenretinide and ABT-263 combined treatment is inducing the expression of Noxa in all four cell lines tested and is largely relying on expression of Noxa.
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Du, Plessis-Stoman Debbie. "A combination of platinum anticancer drugs and mangiferin causes increased efficacy in cancer cell lines." Thesis, Nelson Mandela Metropolitan University, 2010. http://hdl.handle.net/10948/d1016160.
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This thesis mainly deals with some biochemical aspects regarding the efficacy of novel platinum anticancer compounds alone and in combination with mangiferin, as part of a broader study in which both chemistry and biochemistry are involved. Various novel diamine and N-S donor chelate compounds of platinum II and IV have been developed in which factors such as stereochemistry, ligand exchange rate and biocompatibility were considered as additional parameters. In the first order testing, each of these compounds was tested with reference to their “killing” potential by comparing their rate of killing, over a period of 48 hours with those of cisplatin and oxaliplatin. Numerous novel compounds were tested in this way, using the MTT cell viability assay and the three cancer cell lines MCF7, HT29 and HeLa. Although only a few could be regarded as equal to or even better than cisplatin, CPA7 and oxaliplatin, the testing of these compounds on cancer cells provided useful knowledge for the further development of novel compounds. Three of the better compounds, namely Yol 25, Yol 29.1 and Mar 4.1.4 were selected for further studies, together with oxaliplatin and CPA7 as positive controls, to obtain more detailed knowledge of their anticancer action, both alone and when applied in combination with mangiferin. In addition to the above, resistant cells were produced for each of the three different cell lines tested and all the selected compounds, both in the presence and absence of mangiferin. The effects of these treatments on the activation of NFĸB when applied to normal and resistant cell lines were also investigated. All the compounds induced apoptosis in the cell lines tested as well as alter the DNA cycle at one or more phase. Additionally, combination of these compounds with mangiferin enhanced the above-mentioned effects. Mangiferin decreases the IC50 values of the platinum drugs by up to 3.4 times and, although mangiferin alone did not induce cell cycle arrest, the presence of mangiferin in combination with oxaliplatin and Yol 25 shows an earlier and greatly enhanced delay in the S-phase, while cells treated with CPA7, Yol 29.1 and Mar 4.1.4 in combination with mangiferin showed a later, but greatly enhanced delay in the S-phase. It was also found that mangiferin acts as an NFĸB inhibitor when applied in combination with these drugs, which, in turn, reduces the occurrence of resistance in the cell lines. Resistance to oxaliplatin was counteracted by the combination with mangiferin in HeLa and HT29, but not in MCF7 cells, while resistance to CPA7 was only counteracted in the MCF7 cell line. Yol 25 and Mar 4.1.4 did not seem to induce resistance in HeLa and MCF7 cells, but did in HT29 cells, whereas Yol 29.1 caused resistance in HeLa and HT29 cells, but not in MCF7 cells. Finally, an effort was made to evaluate the different compounds by comparing them with respect to their properties relating to anticancer action with and without the addition of mangiferin.
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Anwar, MD Sheikh. "Natural compounds in combination with platinum drugs administered to ovarian cancer models towards synergistic outcomes." Thesis, The University of Sydney, 2018. http://hdl.handle.net/2123/18714.
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Ovarian cancer is known as one of the dreaded diseases due to its low five years’ survival, acquired drug resistance and recurrence. It is treated mainly by platinum drugs given alone or in combination with paclitaxel. However, problems of drug resistance that is often acquired still remain. While resistance to platinum drugs at the molecular level can be due to overexpression of nuclear factor kappa B (NF-κB) and protein kinase B (AKT/PKB) pathways, it is believed that phytochemicals and other natural compounds can inhibit expression of NF-κB and AKT/PKB. This study aimed to apply binary combinations of platinum drugs cisplatin and oxaliplatin with natural compounds mycophenolic acid, honokiol, cholecalciferol and 6-shogaol to four ovarian cancer cell lines: A2780, A2780cisR, A2780ZD0473R and SKOV-3 towards overcoming drug resistance. IC50 values of compounds were first determined before the combination studies. Studies on DNA damage, cellular platinum accumulation and platinum-DNA binding were carried out. Proteomic study has been performed aiming to determine key proteins associated with drug resistance. Mycophenolic acid (IC50: 1.34-7.83 μM) and 6-shogaol (IC50: 6.79-10.20 μM) showed significant activity against ovarian cancer cell lines compared to cisplatin (IC50: 1.18-9.02 μM). 6-shogaol showed synergism in combination with cisplatin and oxaliplatin when administered as a bolus 0/0h and with 0/4 h sequence against A2780, A2780cisR and A2780ZD0473R cell lines. Honokiol alone and in combination with cisplatin caused significant DNA damage in the parent A2780 cell line whereas cholecalciferol did the same to cisplatin-resistant A2780cisR cell line. Concurrent administration of cisplatin and 6-shogaol produced higher cellular platinum accumulation and three times greater platinum-DNA binding than cisplatin in the parent ovarian A2780 cell line. Although (0/0 h) combination of honokiol and cisplatin produced a lower cellular accumulation of platinum, it resulted in greater platinum-DNA binding. Cholecalciferol and 6-shogaol in combination with cisplatin also produced increased platinum-DNA binding in the A2780cisR cell line. Proteomic studies have been performed to explore the proteins involved with drug-resistance in cisplatin-resistant A2780cisR and picoplatin-resistant A2780ZD0473R cell lines. Nineteen proteins were found to be significantly expressed in 23 different spots in untreated A2780cisR and A2780ZD0473R cell lines compared to the expression level observed in the untreated parent A2780 cell line. Selected synergistic combinations of platinum drugs and natural compounds were associated with reduced expression of anti-apoptotic proteins and heightened expression of the pro-apoptotic proteins towards overcoming chemoresistance. 6-shogaol in combination with cisplatin and oxaliplatin had the ability to combat platinum chemoresistance by downregulating the expression of the anti-apoptotic proteins and increasing the expression of the pro-apoptotic proteins in ovarian A2780cisR and A2780ZD0473R cell lines. In summary, ginger derived phytochemical, 6-shogaol alone and in combination with cisplatin and oxaliplatin showed significant cytotoxicity against ovarian cancer tumour models. Therefore, 6-shogaol could be a prospective candidate for combination therapy to manage ovarian cancer in future.
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Gabriels, Gary Anthony. "Determination of the effect of blood testing intervals on bioavailability and bioequivalence assessment of fixed-dose drug combination anti-tuberculosis drugs." Master's thesis, University of Cape Town, 2003. http://hdl.handle.net/11427/3387.
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Svensson, Åsa. "Application of a New Logic to Old Drugs: Angiogenesis Inhibition in Neuroblastoma." Doctoral thesis, Uppsala University, Department of Medical Cell Biology, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3458.
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<p>Neuroblastoma is one of the most common solid cancers of early childhood. In Sweden, approximately 10-15 cases occur annually. The overall five-year neuroblastoma survival in Europe is approximately 45%. Since cancer treatment involves drugs with risks of side effects in the growing child, there is a need for more effective and less toxic drugs. One new approach in cancer treatment is inhibition of tumor angiogenesis, i.e., of new blood vessel growth into the tumor. An angiogenesis inhibitor may be combined with cytostatic drugs to enhance the efficacy. The aim of this study was to investigate how drugs could be used to inhibit angiogenesis and tumor growth in a xenograft model of human neuroblastoma in nude mice. </p><p>The tumors express the angiogenesis stimulator vascular endothelial growth factor (VEGF) on both protein and mRNA levels. The angiogenesis inhibitors SU5416 (an inhibitor of VEGF signalling) and TNP-470 (an inhibitor of endothelial cell proliferation) inhibited angiogenesis in our model. TNP-470, however, inhibited angiogenesis without significant reduction of the tumor growth, in contrast to SU5416. </p><p>We also discovered that the cytostatic drug CHS 828 could cause regression of neuroblastoma tumors in the model when given orally at a low daily dose, alone or in combination with the angiogenesis inhibitor SU5416 or TNP-470. </p><p>Furthermore, a new use of the cardiac glycoside digoxin was found. Digoxin inhibited FGF-2 -stimulated bovine capillary endothelial cell growth in vitro, and inhibited angiogenesis in vivo in the chick chorioallantoic membrane assay (CAM). It also inhibited neuroblastoma growth by approximately 50% in our neuroblastoma model. </p><p>In conclusion, CHS 828 and digoxin represent two classes of drugs with potent antitumor effects that may be valuable in treatment of neuroblastoma, either alone or in combination with angiogenesis inhibitors.</p>
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Chetty, Prakash. "Development and assessment of propranolol sustained release dosage forms separately and in combination with hydrochlorothiazide." Thesis, Rhodes University, 2006. http://eprints.ru.ac.za/1342/.
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Lövgren, Ulf. "Enzyme immunoassay in combination with liquid chromatography for sensitive and selective determination of drugs in biosamples." Lund : Dept. of Analytical Chemistry, Lund University, 1997. http://books.google.com/books?id=Ju1qAAAAMAAJ.
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Radhakrishnan, Suresh. "Enhancement of anti-tumour activity by combination of cytotoxic drugs and replication-selective adenoviruses to target prostate cancer." Thesis, Queen Mary, University of London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.498525.
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Bhattacharya, Bhaskar. "Inhibitors of phosphoinositide 3-kinase (PI3K)/AKT pathway in combination with cytotoxic drugs in human ovarian cancer cell lines." Thesis, Institute of Cancer Research (University Of London), 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.502454.
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Shahiduzzaman, Md. "Combination of cell culture and quantitative PCR (cc-qPCR) for assessment of efficacy of drugs and disinfectants against Cryptosporidium parvum." Doctoral thesis, Universitätsbibliothek Leipzig, 2010. http://nbn-resolving.de/urn:nbn:de:bsz:15-20100316-075533-2.
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Cryptosporidium parvum is an obligatory intracellular parasitic protist that belongs to the phylum Apicomplexa. Cryptosporidiosis is an infection for which no satisfactory efficient curative treatment is known, especially in immunocompromised individuals. Furthermore, the parasite oocysts show considerable tenacity in the environment. Therefore, new potent drugs along with a simple and reliable experimental model for evaluation of anticryptosporidial measures are urgently needed. The present studies were undertaken to establish a combined cell culture and quantitative PCR assay (cc-qPCR) to assess efficacy of pharmacological compounds against C. parvum. Human ileocecal adenocarcinoma cells (HCT-8) were selected for culture of C. parvum. Oocysts were excysted directly on confluent monolayers for infection. After 3 h of incubation the non invasive parasite remains were removed by washing. At the end of the incubation period the cells were harvested and subjected to DNA extraction. Real time PCR was performed to quantify the target parasite DNA (fragments of 70 kDa heat shock protein gene) copy numbers. Each reaction was run in triplicate. A standard curve calculated on the basis of serial dilutions of plasmid DNA or infected control culture DNA was run in each experiment. A series of oocyst suspensions were applied to cell cultures to determine the sensitivity of the cc-qPCR assay and also to generate a calibration curve to calculate the infectivity of oocysts. A dilution series of heat inactivated oocysts (70°C for 1 h) were used to determine the size of the oocyst inoculum at which complete elimination of extracellular parasite material by washing is reliably achieved. The results obtained by the assays were reproducible and the method sensitive with a detection limit of infection with 10 oocysts 48 h post infection (p.i.) and with 100 oocysts 24 h p.i. Percent effects of drugs and disinfectants were enumerated by comparing DNA copies between treated and non treated samples. The suitability of cc-qPCR for screening of pharmacological compounds was validated by confirming the in vitro efficacy of monensin (98.15% ± 1.09 at 0.144 µM) and halofuginone (98.05% ± 0.59 at 25 µM) over the entire incubation period with a dose dependent reduction of parasite multiplication demonstrated 27 h p.i. The inhibition of parasite proliferation by 0.144 µM monensin in the period from 3 h p.i (time defined to represent the initial level of parasite development before drug application) to 27 h p.i. or 45 h p.i. was 97 and 99% respectively, and by 25 µM halofuginone 99% (27 h p.i.). Hexadecylphosphocholine (miltefosine), a new anti-leishmanial compound, was tested against cryptosporidia and provided a maximum of 98% reduction of parasite multiplication at 45 h p.i. The potential activity of curcumin (extract from the herb Curcuma longa) against C. parvum was also evaluated by cc-qPCR. Curcumin appeared to be sensitive to degradation after prolonged incubation and the observed inhibition of multiplication of C. parvum was significantly increased when medium was replaced by fresh medicated medium after 12 h of exposure. The effects on parasite multiplication (>95% inhibition with IC50 value of 13 µM) and on sporozoite invasion (assessed 3 h p.i.; 65% inhibition at 200 µM) suggest that further exploration of anticryptosporidial efficacy of curcumin may be rewarding. The cc-qPCR was further optimized to analyse inactivation measures directed against oocysts of C. parvum. The suitability of the assay for assessment of inactivation measures was confirmed by the reproducible demonstration of effectiveness of cresolic disinfectants at the recommended concentration of 4% and incubation period of 2 h (Neopredisan® 135-1, Menno Chemie, Norderstedt, Germany: 99.91% ± 0.08; Aldecoc® TGE, EWABO Chemikalien GmbH & Co. KG, Wietmarschen, Germany: 99.91± 0.05) and by using thermally inactivated oocysts (complete inactivation by 56°C and 70°C for 20 min). Based on the in vitro results and previously obtained data from the chicken infection model 99.5% inactivation is proposed as a suitable threshold value that needs to be consistently exceeded by a product to be considered efficient. Application of Neopredisan® 135- 1 and Aldecoc® TGE (4% for 2h) consistently inactivated more than 99.5% of oocysts while other disinfectants that are not certified as anticoccidial products like Aldecoc® XD (EWABO Chemikalien GmbH & Co. KG, Wietmarschen, Germany) and IGAVET® FF spezial (COS OHLSEN Chemie & Gerätevertrieb GmbH, Geltorf-Esprehm, Germany) and bleach (sodium hypochlorite) did not. It can be concluded that the cc-qPCR method is suited to easily and reliably assess anticryptosporidials in vitro. The method demonstrated that miltefosine and curcumin display anticryptosporidial efficacy under the applied conditions. The cc-qPCR is a highly standardized method supposedly appropriate to replace the chicken infection model for Eimeria tenella as currently practised for certification of anticoccidial disinfectants according to the guidelines of DVG (German Veterinary Society).
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Sabatino, Maria Antonietta. "Combination treatments in in vitro and in vivo models between molecules reverting epigenetic gene silencing and DNA-interacting anticancer drugs." Thesis, Open University, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.502390.
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Epigenetic transcriptional gene silencing plays a fundamental role in cancer development and has been considered as a target for cancer therapy in the last few years, mainly due to its reversibility by small molecules. Among the several methylated genes investigated, glutathione-S-transferase CGST) PI, a protein belonging to cellular detoxification systems, has been shown to be extensively promoter-methylated in prostate cancer. My study therefore describes a new therapeutic approach against prostate cancer, based on the combination of demethylating agents and brostallicin, a DNA minor groove binding drug, which is activated in the cell by binding to glutathione, a reaction catalyzed by GST. Among the demethylating molecules tested on the prostatic cancer cell line LNCaP in in vitro combinations with brostallicin, zebularine was able to increase brostallicin activity with little toxicity compared to the other tested demethylating drugs. These in vitro results prompted the in vivo testing of zebularine with brostallicin on LNCaP cells transplanted in mice. Prolonged treatment with zebularine was able to significantly improve brostallicin antitumour activity compared to both drugs administrated as single agents. When GSTPI expression was investigated in treated samples versus untreated controls, no protein re-expression was found and this was related to the unchanged levels of GSTPI promoter methylation. In contrast, the demethylating effect of zebularine was clearly evident in the promoter of GSTMI gene, which is also silenced by methylation in LNCaP cells. GSTMI codes for a class of GST. enzymes that has recently been found to be more active on brostallicin than GSTPI. This indicates that the activation of brostallicin cytotoxicity in LNCaP cells by zebularine likely depends on enzymatic activation by GSTMI rather than GSTPI and strengthens the feasibility of this combination as a treatment for prostate cancer in the clinic, and as model for the therapy of other solid tumours.
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Jabbar, Shireen Arjumand Bano. "The response of human lung cancer cell lines to interferons and tumour necrosis factor, alone or in combination with cytotoxic drugs." Thesis, University of Cambridge, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.335163.
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Liu, Fang. "Innovative local delivery of anticancer drugs in combination with an immunomodulatory tumor-targeting monoclonal antibody improves long-lasting antitumor effects in melanoma." Electronic Thesis or Diss., Université de Montpellier (2022-....), 2025. http://www.theses.fr/2025UMONT004.
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L'approbation des inhibiteurs de points de contrôle immunitaires a considérablement amélioré le pronostic des patients atteints de mélanome métastatique, un cancer autrefois associé à l'un des pires pronostics. Cependant, le taux de réponse à ces thérapies reste inférieur à 50 %. Parallèlement, les thérapies ciblées qui visent les mutations les plus courantes (BRAFmut) dans le mélanome ont également transformé le paysage thérapeutique. Ces molécules agissent rapidement sur la croissance tumorale et ont notablement amélioré le taux de survie médian. Cependant, cet effet est souvent de courte durée, car la plupart des patients développent rapidement une résistance. Pour y remédier, des différentes approches thérapeutiques combinées ont été explorées. Cependant, ces combinaisons entraînent souvent une toxicité accrue des traitements. Dans ce contexte, un système d'administration local de ces médicaments qui libérerait les molécules de manière prolongée en favorisant ainsi des concentrations élevées tout en minimisant leur exposition systémique, pourrait améliorer l'efficacité globale du traitement. Suivant cette approche, nous avons conçu des thérapies combinées impliquant l’anticorps monoclonal TA99 (AcM TA99) ciblant le mélanome et des petites molécules anticancéreuses, délivrées via la technologie BEPO®. Des études précédentes dans notre laboratoire ont démontré que l’AcM TA99, ciblant l'antigène associé au mélanome TYRP1, surexprimé à la surface des cellules de mélanome, induisait une protection à long terme sans tumeur et une réponse immunitaire antitumorale mémoire chez 30 % des souris, tandis que les 70 % restantes avaient un retard initial de croissance tumorale, suivi d'un échappement. Ces résultats nous ont conduits à développer des stratégies thérapeutiques combinées pour améliorer le potentiel immunomodulateur de l’AcM TA99. Ainsi, l'objectif global de ma thèse a été d'utiliser un système innovant de délivrance de médicaments pour développer des approches thérapeutiques combinées à l’AcM TA99 afin d’obtenir des réponses antitumorales durables dans le mélanome. La première partie s'est concentrée sur le modèle de mélanome murin B16F10 de type sauvage. Nous avons sélectionné l'imiquimod (IMQ) pour une administration péritumorale en utilisant la technologie BEPO®. L'IMQ est un agoniste synthétique du récepteur de type Toll 7 (TLR7) déjà utilisé en clinique mais limité à une application topique en raison d’effets indésirables potentiellement graves à des concentrations systémiques élevées. En tant que ligand puissant du TLR7, l'IMQ, administré localement, pourrait agir en synergie avec l’AcM TA99. Après la sélection d’une formulation BEPO®IMQ permettant une cinétique de libération optimale, nous avons démontré que la combinaison de BEPO®IMQ injectée par voie péritumorale avec l’AcM TA99 induisait un meilleur contrôle de la croissance tumorale et une amélioration de la survie avec le développement d’une mémoire immunitaire durable. De plus, avec son profil de libération prolongée, BEPO®IMQ s’est révélé plus efficace que la crème AldaraTM, produit commercialisé.La deuxième partie de ma thèse a porté sur la conception de thérapies combinées pour agir en synergie avec l’AcM TA99 dans le mélanome présentant des mutations dans la voie MAPK. Ainsi, nous avons combiné TA99 avec des petites molécules de thérapie ciblée telles que le dabrafenib et le trametinib pour éliminer les cellules cancéreuses avec deux mécanismes distincts, d’autant plus que les agents de thérapie ciblée ont montré une induction de l'expression de TYRP1. Nous avons ainsi démontré que la triple thérapie combinée BEPO®-dabra/trame plus TA99 présentait des effets antitumoraux supérieurs aux monothérapies. La formulation BEPO®-dabra/trame a également été comparée à la prise orale quotidienne des deux molécules dans le cadre de la triple thérapie combinée et a présenté des effets antitumoraux supérieurs dans le contexte de sa combinaison avec l’anticorps TA99<br>The approval of immune checkpoint inhibitors has significantly altered the prognosis for patients with metastatic melanoma, a cancer once associated with one of the poorest outcomes. While effective, the response rate to these therapies remains below 50%. At the same time, targeted therapies aimed at the most common mutations (BRAFmut) in melanoma have also transformed the treatment landscape. These targeted drugs act rapidly on tumor growth and have notably improved median survival rates. However, this effect is often short-lived, as resistance develops quickly in most of patients. To address these challenges, combination of different anti-cancer therapies has been explored. However, these combinations often lead to increased drug toxicity without providing significantly better anti-cancer effects. In this context, local drug delivery systems have been extensively studied to release drugs in a sustained manner with high local concentrations, thereby enhancing drug efficacy while minimizing systemic drug exposure. In line with this approach, we designed combination therapies involving a melanoma-targeting monoclonal antibody (mAb) and small molecule anti-cancer drugs, delivered through the BEPO platform. Previous studies in our laboratory demonstrated that TA99 mAb, targeting the melanoma associated antigen TYRP1 which is overexpressed on melanoma cells, induced a long-term tumor-free protection and an antitumoral immune memory response in 30% of the mice, whereas the 70% remaining animals had an initial delay in tumor growth, followed by tumor escape. These results prompted us in the development of combined therapeutic strategies to reinforce the immunomodulatory potential of TA99 mAb. Thus, the global objective of my thesis was to use an innovative drug delivery system to develop combined TA99 mAb-dependent therapeutic approaches, aimed at modifying the tumor immune landscape and enhancing long-lasting antitumor responses in melanoma. The first aim focused on designing combination therapies to synergize with TA99 mAb in the wild type B16F10 syngeneic melanoma model. We selected imiquimod (IMQ) for peritumoral delivery using BEPO technology. IMQ is a synthetic toll-like receptor 7 (TLR7) agonist already used in clinic but restrained to topical application due to potential severe immune-mediated adverse effects at high systemic concentrations. As a potent ligand to TLR7, IMQ induces the production of type I interferon and proinflammatory cytokines and could synergize with TA99 mAb upon local delivery. Following the selection of the BEPOIMQ formulation with the optimal IMQ release kinetic, we demonstrated that the combination of peritumoral BEPOIMQ with TA99 mAb induced a better control on tumor growth and an improved survival with the development of an endogenous antitumoral immune response and a long-lasting immune memory. Moreover, with its sustained release profile, BEPOIMQ was more potent than the approved product AldaraTM cream.The second aim of my thesis focused on designing combination therapies to synergize with TA99 mAb in the melanoma harboring mutations in the MAPK pathway. For this purpose, we aimed at combining TA99 mAb with targeted therapy small molecules such as dabrafenib and trametinib to eliminate cancer cells with two distinct mechanisms. Importantly, targeted therapy agents have shown to induce the melanocytic antigen expression, which indicates potential synergistic anti-tumor effects when combined with TA99 mAb. Indeed, we demonstrated that the triple combination therapy BEPO-dabra/trame plus TA99 mAb exhibited superior anti-tumor effects, including a better tumor growth control, an increased number of tumor-free mice, and improved survival. BEPO-dabra/trame was also compared with the daily oral uptake of dabrafenib and trametinib in the triple combination therapy setup and the long-acting formulation presented superior anti-tumor effects in the context of its combination with TA99mAb
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Do, Monte Fialho Murteira Susana Claudia. "Drug repurposing and market access : conditions and determinants for price, reimbursement and access of reformulated and repositioned drugs in the United States of America and Europe." Thesis, Lyon 1, 2014. http://www.theses.fr/2014LYO10115.
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Le développement de novo de médicaments est un processus long et coûteux. De plus en plus, les développeurs de médicaments cherchent à mettre en oeuvre des stratégies rentables et à moindre risque pour le développement de produits pharmaceutiques. Le processus de trouver de nouveaux usages pour des médicaments existants en dehors de l'indication initiale pour laquelle ils ont été initialement approuvé est couramment désigné comme « repositionnement », « réorientation » ou « reprofilage ». Le développement de formulations différentes pour un même médicament pharmaceutique est communément désigné comme « reformulation » et le processus de trouver une autre utilisation thérapeutique d'un médicament déjà connu est dénommé « repositionnement ». Ces deux stratégies sont devenues un courant dominant dans le développement des médicaments. Les principaux objectifs de la recherche menée dans cette thèse sont de parvenir à proposer une nomenclature et la taxonomie solide et valable pour l'identification et la classification des stratégies de « repurposing » de médicaments ; évaluer les voies de régulation de stratégies de repositionnement et de reformulation, par types de stratégies et dans les 2 régions géographiques étudiées ; et déterminer les paramètres qui ont un impact sur la probabilité d'un résultat positif sur le prix, le remboursement et l'accès au marché vis-à-vis des conditions accordées pour le médicament original dans les deux régions géographiques dans l'étude<br>De novo drug development is a costly and lengthy process. As a result of such market forces, drug developers are increasingly striving to find cost effective and reduced-risk strategies for developing drug products and to protect existing products from competition, as well as to extend their patent protection time. The process of finding new uses for existing drugs outside the scope of the original indication for which they were initially approved is variously referred as repositioning, redirecting, repurposing, or reprofiling. The development of different formulations for a same pharmaceutical drug is commonly designated as “reformulation” and the process of finding a new therapeutic use for an already known drug is referred to as “repositioning”. Both strategies have become a mainstream in drug development. The main objectives of the research conducted in this thesis are to propose a robust and valid nomenclature and taxonomy for identification and classification of drug repurposing strategies, to evaluate which regulatory pathways and trends are taken by drug repositioning and reformulation, by repurposed types and within the Europe and the US and determine which parameters have the most and least impact on the probability of a successful outcome on pricing, reimbursement and market access in repurposing vis-à-vis the conditions granted for the original drug
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Pang, Christina Lynn. "Effects of Inhaled Combination Corticosteroid Drugs on Aerodynamic Measures of Phonation and Visual-Perceptual Measures of Vocal Fold and Arytenoid Tissue in Excised Rabbit Larynges." BYU ScholarsArchive, 2021. https://scholarsarchive.byu.edu/etd/8934.
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The purpose of this thesis is to examine the effects of inhaled corticosteroid drugs (ICs) on the voice due to their frequent use in treating an increasing prevalence of asthma disorders. As part of a larger five-year study, the focus of this thesis is specifically on whether 8 weeks of in vivo exposure to ICs will cause changes in the sustained subglottal pressure, sustained airflow, and visual-perceptual ratings of edema and erythema in excised rabbit larynges. Researchers administered either ICs or a control nebulized isotonic saline solution to 22 rabbits in vivo, sacrificed them, and harvested their larynges for benchtop research. While ensuring proper tissue preservation, researchers then finely dissected the larynges to expose the true vocal folds and run phonation trials. Dependent variables included continuous acoustic signals (Hz), subglottal pressure (cm H2O), and airflow (L/min) data for 15 phonation trials per rabbit larynx. Researchers also collected still image photographs at this time and subsequently normalized them for use in the visual-perceptual portion of this thesis. For visual-perceptual ratings, raters used a 0-3 equal appearing interval scale to rate aspects of edema and erythema on left and right vocal fold and arytenoid tissues. Results indicate that, when compared to control larynges exposed to nebulized isotonic saline, experimental larynges treated with ICs require significantly higher subglottal pressure to maintain phonation, p < .05. Mean sustained phonation for experimental larynges is 11.24 cm H2O compared to 8.92 cm H2O for that of control larynges. Phonation trials for experimental larynges have significantly higher sustained airflow with a mean of 0.09 L/min compared to 0.07 L/min for that of control larynges, p < .05. Surprisingly, experimental larynges have higher average fundamental frequencies with less variability (mean: 519 Hz, standard deviation: 66 Hz) than that of control larynges (mean: 446 Hz, standard deviation: 130 Hz). On visual-perceptual ratings, experimental larynges have significantly higher severity ratings on all eight items rated, p < .0001 - p = .0305. Based on these results, it is concluded that ICs cause significant damage to rabbit vocal folds, as evidenced by higher sustained pressure, higher airflow, and higher severity ratings for experimental versus control larynges. The dependent variables in this thesis are novel in benchtop model research and demonstrate a unique perspective on this research question. Thus, this thesis informs future phonation, benchtop, and visual-perceptual research.
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Momodu, Rametu Omamegbe. "Knowledge and practices of patent medicine vendors in the use of artemisinin based combination therapy in the treatment of malaria in an urban community in Lagos." Thesis, University of the Western Cape, 2008. http://etd.uwc.ac.za/index.php?module=etd&action=viewtitle&id=gen8Srv25Nme4_2704_1271017667.
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<p>Malaria is a health, social and economic burden in Nigeria and consistently ranks amongst the four most common causes of childhood deaths. Treatment of malaria is usually started at home<br>care is only sought from the health facility when the treatment is ineffective (McCombie, 1996). Patent medicine vendors (PMVs) have been identified as a widely patronized source for drugs used in the home treatment of malaria (Breiger et al, 2001<br>Goodman, et al, 2007<br>Salako et al, 2001). Inadequate or poor knowledge and practices in the use of anti-malaria drugs (AMDs) increases morbidity and mortality, undermines therapeutic efficacy, and promotes the emergence and spread of drugresistant malaria. Aim: The aim of the study was to describe and quantify the knowledge and self-reported practices of PMVs in the use of antimalarials, particularly artemisinin-based combination therapies (ACTs), in a poor urban community in Lagos state, Nigeria.</p>
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Zikusooka, Charlotte Muheki. "Evaluating the cost-effectiveness of artemisinin-based combination antimalarial drugs and malaria rapid diagnostic tests within the context of effective vector control : case study of Southern Africa." Doctoral thesis, University of Cape Town, 2006. http://hdl.handle.net/11427/7439.
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Includes bibliographical references (p. 253-265)<br>This study seeks to use the techniques of cost-effectiveness analysis to evaluate, within the context of effective vector control, the change to artemisinin-based combination therapies (ACTs) as first line malaria treatment and to evaluate the relevance of using definitive diagnosis (as opposed to clinical diagnosis) as the basis for initiating malaria treatment, especially when using ACTs for treatment. The cost-effectiveness of ACTs was evaluated in two study sites (i.e. In Kwazulu Natal which switched from SP monotherapy to AL in 2001 and in Mpumalanga which changed from SP monotherapy to AS+SP in 2003) in South Africa. The economic evaluation of use of routine definitive diagnosis as part of malaria case management, using rapid diagnostic tests (ROTs), was undertaken at two districts (Namaacha and Matutuine), in southern Mozambique, where routine use of ROTs and treating malaria patients with an ACT (using artesunate + SP) were implemented at pilot level in 2003.
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Mojica, Muñoz Ann-Katrin [Verfasser], and Wolfgang [Akademischer Betreuer] Siess. "Effect of GPVI-Fc in combination with standard antiplatelet drugs and of GPVI-Fc fused to CD39 on platelet thrombus formation / Ann-Katrin Mojica Muñoz ; Betreuer: Wolfgang Siess." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/1196009104/34.
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Соцька, Я. А., І. О. Шаповалова, І. М. Баскаков, Л. П. Антонова та Р. А. Нужний. "Вплив комбінації циклоферону і зітрокса на ефективність лікування хворих з тяжким перебігом гострого тонзиліту". Thesis, Сумський державний університет, 2014. http://essuir.sumdu.edu.ua/handle/123456789/37934.
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У даний час відзначається суттєве збільшення частоти захворювання пацієнтів тяжкими формами гострого тонзиліту, а також і іншими стрептококовими інфекціями.
Метою роботи було вивчення впливу комбінації зітрокса і циклоферона на біохімічні та імунологічні показники у хворих з тяжким перебігом гострого тонзиліту.
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Abrahams, Beynon. "The effects of various combinations of different classes of anticancer drugs and tyrosine kinase inhibitors on the human MCF-7 breast carcinoma cell line." Thesis, University of the Western Cape, 2014. http://hdl.handle.net/11394/3846.
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Magister Scientiae (Medical Bioscience) - MSc(MBS)<br>This study investigated the effects of TKIs on the growth and proliferation of MCF-7 breast carcinoma cells in culture. MCF-7 cells were exposed to different concentrations of TKIs alone and in combination with each other. Inhibition of cell growth by TKIs used individually occurred in a dose- and time-dependent manner. When EGFR Inhibitor I, EGFR Inhibitor II/BIBX1382 and the multi-specific EGFR/ErbB-2/ErB-4 Inhibitor were used in combination with each other at equimolar log dose concentrations, the combined effects on cell growth was significantly different to inhibitors used individually as reflected in a decreased EC50 (IC50) during combination treatments. Generally, for the combinations with DOX, CPL and the TKIs, synergistic as well as antagonistic effects were observed at isoeffective concentrations with resultant decreases in dose reduction indices (DRIs) implying greater efficacies with the respective combinations. In this study, conventional PCR was used to detect and illustrate the presence of the EGFR gene in the samples, while RT-qPCR was used to determine the mRNA expression levels of this gene in MCF-7 breast carcinoma cells
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Haddad, Tarek [Verfasser], and Klaus [Akademischer Betreuer] Kümmerer. "The Fate of Antibiotics and Anticancer Drugs in the Aquatic Environment - Evaluating the Photolysis of Ciprofloxacin and Monitoring the Course of its Genotoxicity by a Combination of Experimental and In Silico Testing / Tarek Haddad. Betreuer: Klaus Kümmerer." Lüneburg : Universitätsbibliothek der Leuphana Universität Lüneburg, 2016. http://d-nb.info/1102524395/34.
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Kao, Lie-Jane. "Designs for drug combination experiments /." The Ohio State University, 1994. http://rave.ohiolink.edu/etdc/view?acc_num=osu14878493772931.
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Khaleel, Nareman Dahshan Henedaq [Verfasser], Klaus [Akademischer Betreuer] Kümmerer, Ralf [Gutachter] Ebinghaus, and Carolin [Gutachter] Floeter. "Fate of psychotropic drugs in the aquatic environment : Assessment of dead-end photo-degradation products generated under varying conditions by combination of experimental and "in-silico" methods / Nareman Dahshan Henedaq Khaleel ; Gutachter: Ralf Ebinghaus, Carolin Floeter ; Betreuer: Klaus Kümmerer." Lüneburg : Leuphana Universität Lüneburg, 2021. http://d-nb.info/1237497469/34.
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Tsai, Hsing-Chuan. "Optimal designs for drug combination experiments /." The Ohio State University, 2000. http://rave.ohiolink.edu/etdc/view?acc_num=osu1488193272068802.
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Omollo, Charles. "Developing methods to prioritize in vitro drug combinations against Mycobacterium tuberculosis: fusidic acid as potential combination partner with known antitubercular agents." Doctoral thesis, University of Cape Town, 2017. http://hdl.handle.net/11427/25432.
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The tuberculosis (TB) epidemic remains a major threat to public health globally, and is exacerbated by the escalating number of multi-drug resistant cases. These factors have highlighted the urgent need for new effective therapies or different approaches to augment the efficacy of current anti-TB drugs. Synergistic drug combinations present a feasible strategy towards expanding TB treatment options. Despite reported successes with combination screening, as well as the current reliance on combination therapy for TB, this approach remains largely underexplored. Evidence suggests that utilizing synergistic combinations might enable existing clinically-approved drugs to be readily re-purposed for TB treatment, including against multi-(MDR) and extensively- (XDR) drug resistant strains for current therapies are often ineffective. This thesis focused on the development and application of improved methods to identify and advance novel drug combinations for TB therapy. There were two key aspects to this work: firstly, exploring mechanisms of synergy between fusidic acid (FSA), a natural product antibiotic, and current anti-TB agents and, secondly, characterizing antibiotic action by delineating bacteriostatic and bactericidal compounds.
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Tam, Stanton Sui Yin. "Anticancer Drug Combinations to Overcome Drug Resistance in Breast Cancer." Thesis, The University of Sydney, 2022. https://hdl.handle.net/2123/27733.
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For triple negative breast cancer (TNBC) patients, taxanes are the mainstays of chemotherapy but remain susceptible to resistance. Combination therapy of paclitaxel/docetaxel and tyrosine kinase inhibitors (TKIs) improves overall response rates in TNBC patients. Ixabepilone, mechanistically similar to taxanes, shows efficacy in TNBCs refractory to paclitaxel/docetaxel. Yet, there is a lack of studies on ixabepilone-TKI combinations. The first aim was to investigate the efficacy of these combinations in docetaxel-resistant MDA-MB-231 (TXT) cells and parental non-resistant MDA-MB-231 (231C) cells.
In preliminary studies, ixabepilone, vandetanib and gefitinib monotherapy inhibited proliferative activity in both cell lines. Vandetanib and ixabepilone showed drug synergism and increased inhibition of cell proliferation. Gefitinib and ixabepilone demonstrated drug antagonism and reduced cell proliferation. Annexin V-FITC/7AAD staining demonstrated increased cell killing after vandetanib-ixabepilone treatment and ascertained apoptosis as the mechanism of cell death in both cell lines. It revealed that vandetanib increases apoptosis when in combination compared to ixabepilone alone. This was supported by Western blotting which yielded altered protein expression of apoptotic players, cleaved-caspase-3 and Bcl-2.
The second aim was to determine how the vandetanib-ixabepilone combination induces apoptosis and overcomes resistance in both cell lines. Using Western blotting, it was determined that vandetanib does not contribute to increased cell death via microtubule stabilisation – the principal apoptotic mechanism of ixabepilone. Instead, in 231C and TXT cells, vandetanib increased proapoptotic NOXA and PUMA respectively.
This thesis reveals a novel combination with antiproliferative/apoptotic activity in docetaxel-resistant and non-resistant TNBC cell lines and lays the foundation for more combinations to overcome resistance and provide novel therapies for TNBC patients.
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Farebrother, Joanna E. "Statistical design and analysis of factorial combination drug trials." Thesis, University of Reading, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.264855.
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MAUCERI, MATTEO. "New Targeted Molecules for the Therapy of Ovarian Cancer." Doctoral thesis, Università degli Studi di Trieste, 2022. http://hdl.handle.net/11368/3031106.
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Patients with high-grade serous ovarian cancer (HGSOC), the most aggressive epithelial ovarian cancer (EOC) subtype, have a 5-year survival rate of about 93% when diagnosed at an early stage, but it drops to 30-40% when diagnosed in the advanced stage. HGSOC aggressiveness is mainly caused by the late diagnosis (51% stage III, 29% stage IV) when the tumor has already spread in the peritoneal cavity. PIN1 is a unique peptidyl-prolyl isomerase that targets the phosphorylated Ser/Thr(Pro) motifs to regulate several key proteins in different signaling pathways. Pin1 is overexpressed in several cancer types and it regulates more than 40 oncogenes and 20 tumor suppressors. Many functions are modulated through PIN1-mediated isomerization such as cell cycle progression, cellular proliferation, invasion, migration, and apoptosis. Downregulation of Pin1 decreases tumor progression. Recently, Pin1 was shown to be overexpressed in ovarian cancer (OC) which, together with the high number of interactions with other proteins, makes Pin1 a promising target for HGSOC. The aim of this work is to investigate the effects of the PIN1 inhibitor VS10 on cancer cell lines and to find the molecular signaling pathways in which Pin1 is involved. Migration, mesothelial clearance assay, and the effects on spheroid formation and preformed spheroids were studied to better understand the effects on the metastatic process. Furthermore, in order to clarify the molecular mechanism that triggers the cytotoxicity induced by Pin1 inhibition in several OC cell lines, silencing Pin1 has been demonstrated to be associated with Ser473pAkt dephosphorylation by Western Blot (WB) analysis. Additionally, cell viability and colony-forming assays showed that Akt overexpression rescued the lethal phenotype due to Pin1 knockdown in OVCAR3 and KURAMOCHI OC cell lines. Among PIN1 inhibitors, All-trans retinoic acid (ATRA), a drug in clinic for the treatment of acute promyelocytic leukemia, has been demonstrated to be active on PIN1. Our group developed many PIN1 inhibitors including VS10, a non-covalent and selective molecule, which is active in killing cancer cells. ATRA and VS10 have been combined with first- and second-line chemotherapy drugs to treat SKOV3 cell line whether these drug combinations could work synergistically to improve current therapy. This drug combination screening showed that Doxorubicin and Caelyx act in synergy with both VS10 and ATRA. This drug combination was studied in 5 sensible and 2 OC cell lines resistant to cisplatin treatment. These results candidate Pin1 as a promising new molecular target for HGSOC patients' therapy.<br>Patients with high-grade serous ovarian cancer (HGSOC), the most aggressive epithelial ovarian cancer (EOC) subtype, have a 5-year survival rate of about 93% when diagnosed at an early stage, but it drops to 30-40% when diagnosed in the advanced stage. HGSOC aggressiveness is mainly caused by the late diagnosis (51% stage III, 29% stage IV) when the tumor has already spread in the peritoneal cavity. PIN1 is a unique peptidyl-prolyl isomerase that targets the phosphorylated Ser/Thr(Pro) motifs to regulate several key proteins in different signaling pathways. Pin1 is overexpressed in several cancer types and it regulates more than 40 oncogenes and 20 tumor suppressors. Many functions are modulated through PIN1-mediated isomerization such as cell cycle progression, cellular proliferation, invasion, migration, and apoptosis. Downregulation of Pin1 decreases tumor progression. Recently, Pin1 was shown to be overexpressed in ovarian cancer (OC) which, together with the high number of interactions with other proteins, makes Pin1 a promising target for HGSOC. The aim of this work is to investigate the effects of the PIN1 inhibitor VS10 on cancer cell lines and to find the molecular signaling pathways in which Pin1 is involved. Migration, mesothelial clearance assay, and the effects on spheroid formation and preformed spheroids were studied to better understand the effects on the metastatic process. Furthermore, in order to clarify the molecular mechanism that triggers the cytotoxicity induced by Pin1 inhibition in several OC cell lines, silencing Pin1 has been demonstrated to be associated with Ser473pAkt dephosphorylation by Western Blot (WB) analysis. Additionally, cell viability and colony-forming assays showed that Akt overexpression rescued the lethal phenotype due to Pin1 knockdown in OVCAR3 and KURAMOCHI OC cell lines. Among PIN1 inhibitors, All-trans retinoic acid (ATRA), a drug in clinic for the treatment of acute promyelocytic leukemia, has been demonstrated to be active on PIN1. Our group developed many PIN1 inhibitors including VS10, a non-covalent and selective molecule, which is active in killing cancer cells. ATRA and VS10 have been combined with first- and second-line chemotherapy drugs to treat SKOV3 cell line whether these drug combinations could work synergistically to improve current therapy. This drug combination screening showed that Doxorubicin and Caelyx act in synergy with both VS10 and ATRA. This drug combination was studied in 5 sensible and 2 OC cell lines resistant to cisplatin treatment. These results candidate Pin1 as a promising new molecular target for HGSOC patients' therapy.
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Muangnoicharoen, Sant. "The clinical pharmacology of artemisinin based drug combinations." Thesis, University of Liverpool, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.502574.
Full textAbstract:
This thesis focuses on the clinical efficacy, pharmacokinetics and pharmacodynamics of artemisinin based drugs and their combinations for their treatment of P. falciparu11l malaria. The aims of the thesis are to get a better understanding of the basic pharmacology of artemisinin type drugs and their combinations. Chapter I is introduction and general knowledge about malaria disease, antimalarial drugs, treatment and drugs resistance. Chapter 2 determines parasite drug susceptibility and drug interaction of dihydroartemisinin and the quinoline type drug, piperaquine, used together as a fixed dose drug combination against P. falciparu11l in vitro. The results show that P. falciparu11l is highly susceptible to these two drugs even though when used in combination they show slight antagonism. Using a set of genetically manipulated parasites the data also showed a clear role for mutations in pferl to confer cross resistance to piperaquine and chloroquine. Chapter 3 focuses on the development of methods to accurately measure artesunate and dihydroartemisinin levels in human plasma. The method was highly sensitivity, robust and importantly reproducible. This method was subsequently used for th.e measurement of artemisinin type drug concentrations throughout my research.
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Chaerunisaa, Anis Yohana [Verfasser]. "Release adjustment of drug combinations with different drug solubility / Anis Yohana Chaerunisaa." Berlin : Freie Universität Berlin, 2014. http://d-nb.info/1048327388/34.
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Harrison, Luke Robert Edward. "Optimising treatment with combinations of novel anti-kinase drugs and cytotoxic therapy." Thesis, University of Newcastle upon Tyne, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.489290.
Full textAbstract:
Aim: To investigate the mechanism of potentiation of cytotoxic drugs by NU2058 (06-cyclohexylmethyl guanine), which had been synthesised as a cyclin-dependent kinase 2 (CDK2) inhibitor. One hundred and forty four structurally related compounds to NU2058 were screened for their ability to potentiate cisplatin cytotoxicity in SQ20b human cancer cells. Sixty six compounds> increased cisplatin cytotoxicity; however, no relationship between CDK2 enzyme inhibition (assessed by immunoblotting for phospho_Rb1 821 protein - a target of CDK2) and cisplatin potentiation was observed. Compound NU6242 was identified as being 10-fold more potent potentiator of cisplatin than NU2058. This was confirmed using LoVo tumour cells. . I They did not potentiate cisplatin despite inhibiting CDK2. A screen of purified' Compounds NU6230 and NU6094 were structural similar to NU2058 and NU6242. kinases identified AMP-activated protein kinase as a possible target ofNU6242. NU2058 (100 ~M) was non-toxic to SQ20b cells. NU2058 only increased cisplatin cytotoxicity (LCso dose modification factor (DMF) of 3.8), when present simultaneously with cisplatin. NU2058 increased cytotoxicity of carboplatin (DMF 2.7), oxaliplatin (DMF 1.8), and melphalan (DMF 2.2), but not temozolomide or ionising radiation.
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Najem, Ahmad. "Drug combination strategies to abrogate resistance in NRAS mutant melanoma." Doctoral thesis, Universite Libre de Bruxelles, 2017. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/258096.
Full textAbstract:
Melanoma is the deadliest form of skin cancer and one of the most difficult cancers to treat. Gene alterations identified in melanoma pointed to distinct molecular subsets of tumors with direct implications in therapeutic strategies. Activating mutations in NRAS, found in 20-30% of melanomas have been associated with aggressive clinical behavior and a poor prognosis. Nevertheless, there is lack of effective targeted therapies for NRAS mutant melanoma.Out of the few MEK inhibitors, pimasertib, a potent inhibitor of both MEK1 and MEK2 has showed promising results in NRAS mutant advanced melanoma. However, as a single agent and similar to other MEK inhibitors, it showed a limited clinical benefit due to its rather cytostatic effect and high toxicity. Our and other preliminary studies clearly indicated a stimulation of MITF (Microphthalmia associated transcription factor), the master transcription factor regulating cell growth and differentiation in the melanocyte, under MEK inhibition challenge. Thus, in a context where the tumor suppressor p53 is largely inactivated in melanoma, the stimulation of MITF may be the cause of the restraint cytotoxic effects of MEK inhibitors. Therefore, we aimed to further investigate the downstream MITF targets that can explain the resistance to the drugs.First, we showed that, MEK inhibition (by Pimasertib) led to a significant inhibition of cell proliferation but with a very limited effect on apoptosis that may be explained by the systematic MITF upregulation in all lines tested. Indeed, Mimicking MITF activation of expression by stimulating cAMP conferred resistance to MEK inhibition and interestingly up-regulated Bcl-2 expression. Further evidence was provided by the fact that, acquired resistance to MEK inhibition is associated with substantial upregulation of the anti-apoptotic signaling MITF/Bcl-2. More importantly, selective Bcl-2 inhibition by ABT-199 or Bcl-2 knock out using CRISPER/Cas9 system restores the sensitivity of NRAS mutant melanoma cells to MEK inhibition and breaks the acquired resistance.Given the known p53 regulating effect on Bcl-2, we evaluated p53 reactivation by PRIMA-1Met (APR-246) under MEK inhibition on the promotion of apoptosis in a panel of Q61NRAS mutant melanoma cells. Strikingly and similarly, this combination not only resulted in a synergistic effect to induce massive apoptosis but also broke resistance to MEK inhibitors both in cells with wild type or mutant p53 alike.In conclusion, we showed that the activation of cAMP/MITF/Bcl-2 pathway is a main anti-apoptotic mechanism associated with resistance to MEK inhibition in NRAS mutant melanoma. We propose drug combinations cotargeting MEK and other proteins regulating apoptosis -p53/Bcl-2- as a promising and clinically relevant therapeutic strategy to not only act in synergy to cause massive apoptosis but also to overcome resistance to MEK inhibitors in NRAS mutant melanoma<br>Doctorat en Sciences biomédicales et pharmaceutiques (Pharmacie)<br>info:eu-repo/semantics/nonPublished
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Obszynska, Jolanta Agnieszka. "Investigations of genomic changes induced by the FAC drug combination." Thesis, University of Leicester, 2003. http://hdl.handle.net/2381/30768.
Full textAbstract:
At the present, researchers are not able to predict which individual patients might be susceptible to developing AML. Current research carried out in various laboratories is focused on identifying potential markers that would allow for identification of such patients. The analysis of gene expression profiles of cells treated with the FAC drug regime gave an insight on the impact that the chemotherapeutics have on non-cancerous cells. Exposure to the FAC drug regime caused many changes in gene expression profiles of treated cells. Experiments examining the impact of single doses treatments and combined FAC regime showed variations in gene expression responses to the xenobiotics. Gene expression profiles varied depending on the amount of time that the cells were exposed to the FAC drugs. Shorter exposure to FAC drugs generated more overexpresed genes. During the microarray analysis, synergistic interactions between FAC drugs were discovered. Such synergistic interactions could be very important for future drug discovery and population studies. Two candidate biomarkers were also investigated as potential indicators of susceptibility to developing secondary leukaemias. Minisatellite MS1 and MLL/AF4 translocations were analysed. Minisatellites are highly sensitive repeat regions in human genome that might be susceptible to changes induced by xenobiotics. MS1 has a highly variable internal structure, because of its variability and unstable nature, it was chosen to act as biomarker. An alternative method to detect DNA damage by identification of MLL/AF4 translocations was explored in this project. Chromosomal aberrations between those genes may cause secondary leukaemeia in cancer patients. PCR based techniques were utilised to detect any MLL/AF4 translocations present both in cell lines and in patients' DNA. Both minisatellites MS1 and MLL/AF4 translocations proved not to be suitable candidates as biomarkers.
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Sgueglia, Umberto. "Predicting Novel Drug-drug Interactions based on structured knowledge in combination with text mining approaches." Master's thesis, Alma Mater Studiorum - Università di Bologna, 2018. http://amslaurea.unibo.it/15494/.
Full textAbstract:
Molto spesso le persone in cura presso gli ospedali possono soffrire di strani effetti collaterali di cui non si conosce minimamente l’origine. In alcuni casi questo può derivare da una sbagliata prescrizione di medicinali al paziente.
Ben noto nella medicina sono gli effetti che una medicina può causare somministrata con un altra allo stesso tempo. Quello che non si conosce, è il risultato di una somministrazione multipla, ovvero quando più medicinali
vengono somministrati contemporaneamente.
Il problema che vogliamo affrontare in questa tesi è quello di capire se sia
possibile usare le informazioni che abbiamo sulle interazioni tra due medicine,
e cercare di costruire un calssificatore in grado di predirre interazioni tra più
medicine nel caso in cui queste possano portare ad effetti collaterali.
Alla base di questo procedimento si trovano le informazioni che chiamer-
emo pair information, ovvero quelle riguardanti due medicine. Date queste
proveremo ad estendere il concetto ad interazioni multiple di medicine.
Come punto di partenza per la ricerca è stata scelta una lista di 77
medicine candidate, le più prescritte durante lo scorso anno in Germania.
Come vedremo successivamente sono state utilizzate fonti di dati strut-
turati e non per cercare di dare maggiore significato di quello che già posse-
diamo per quanto riguarda le pair interaction.
Come vedremo dalla valutazione, la combinazione di elementi derivanti
dal text mining e dati fortemente non strutturati, con elementi invece strut-
turati e verificati può portare risultati davvero interessanti.
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Regan-Fendt, Kelly E. "Integrative Network and Transcriptomics Approach Enables Computational Drug Repurposing and Drug Combination Discovery in Melanoma." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1521209048981327.
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Schmitt, Christina Verfasser], Kirsten [Akademischer Betreuer] [Hattermann, and Regina [Gutachter] Scherließ. "Influence of neuroimplant materials, drugs and drug-material combinations on healthy cells of the brain / Christina Schmitt ; Gutachter: Regina Scherließ ; Betreuer: Kirsten Hattermann-Koch." Kiel : Universitätsbibliothek Kiel, 2020. http://nbn-resolving.de/urn:nbn:de:gbv:8-mods-2020-00182-0.
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