subject:(pharmacodynamics)

University of Manchester

1. Jeans, Adam Rupert. The Pharmacodynamics of Antifungal Agents Against Aspergillus.

Degree: 2013, University of Manchester

URL: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:212715

► Background: Voriconazole is a first line agent for the treatment for invasive pulmonary aspergillosis. There are increasing reports of Aspergillus fumigatus isolates with reduced susceptibility… (more)

▼ Background: Voriconazole is a first line agent for the treatment for invasive pulmonary aspergillosis. There are increasing reports of Aspergillus fumigatus isolates with reduced susceptibility to voriconazole. I investigated the pharmacodynamics of voriconazole against drug susceptible and drug resistant strains of Aspergillus fumigatus through the development of a novel dynamic in vitro model of the human alveolus. I then investigated whether combination therapy with voriconazole and anidulafungin would be beneficial in the treatment of infection with these isolates.Methods: An in vitro dynamic model of IPA was developed that enabled simulation of human-like voriconazole pharmacokinetics. Galactomannan was used as a biomarker. The pharmacodynamics of voriconazole against wild-type and three resistant strains of A. fumigatus were defined. The results were bridged to humans to provide decision support for setting breakpoints for voriconazole using Clinical Laboratory Standards Institute (CLSI) and European Committee of Antimicrobial Susceptibility Testing (EUCAST) methodology. The interaction of voriconazole and anidulafungin in an in vitro static model was described using the Greco model.Results: Isolates with higher MICs required higher area under the concentration time curve (AUCs) to achieve suppression of galactomannan. An AUC:MIC using CLSI and EUCAST methodology that achieved suppression of galactomannan was 55 and 32.1, respectively. A trough concentration:MIC using CLSI and EUCAST methodology that achieved suppression of galactomannan was 1.68 and 1, respectively. Potential CLSI breakpoints for voriconazole are: susceptible ≤ 0.5 mg/L; resistant > 1 mg/L. Potential EUCAST breakpoints for voriconazole are: susceptible ≤ 1 mg/L; resistant > 2 mg/L. Galactomannan concentrations were only marginally reduced by anidulafungin monotherapy in the static model. An additive effect between voriconazole and anidulafungin was apparent.Conclusions: Voriconazole resistance mechanisms can be overcome with higher drug exposures, but this may require concentrations likely to cause toxicity in humans. The addition of anidulafungin does not markedly alter the exposure-response relationship of voriconazole. A rise in serum galactomannan during combination therapy with voriconazole and anidulafungin should be interpreted as treatment failure and not attributed to a paradoxical reaction related to echinocandin treatment. The dynamic in vitro model is a useful tool to address many remaining questions related to treatment of invasive fungal infection. Advisors/Committee Members: HOPE, WILLIAM WWD, Hope, William, Richardson, Malcolm.

Subjects/Keywords: Aspergillus; Pharmacodynamics; Voriconazole; Anidulafungin

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Jeans, A. R. (2013). The Pharmacodynamics of Antifungal Agents Against Aspergillus. (Doctoral Dissertation). University of Manchester. Retrieved from http://www.manchester.ac.uk/escholar/uk-ac-man-scw:212715

Chicago Manual of Style (16^th Edition):

Jeans, Adam Rupert. “The Pharmacodynamics of Antifungal Agents Against Aspergillus.” 2013. Doctoral Dissertation, University of Manchester. Accessed February 27, 2021. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:212715.

MLA Handbook (7^th Edition):

Jeans, Adam Rupert. “The Pharmacodynamics of Antifungal Agents Against Aspergillus.” 2013. Web. 27 Feb 2021.

Vancouver:

Jeans AR. The Pharmacodynamics of Antifungal Agents Against Aspergillus. [Internet] [Doctoral dissertation]. University of Manchester; 2013. [cited 2021 Feb 27]. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:212715.

Council of Science Editors:

Jeans AR. The Pharmacodynamics of Antifungal Agents Against Aspergillus. [Doctoral Dissertation]. University of Manchester; 2013. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:212715

University of Manchester

2. Felton, Timothy. Antimicrobial therapy in critically ill patients: Improving clinical outcomes using a translational pharmacological approach.

Degree: 2014, University of Manchester

URL: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:235681

►

Pulmonary infections in critically ill patients are common, frequently lethal and treatment may be complicated by bacterial resistance. Piperacillin-tazobactam (PTZ) is a broad-spectrum β-lactam antibiotic,… (more)

▼

Pulmonary infections in critically ill patients are common, frequently lethal and treatment may be complicated by bacterial resistance. Piperacillin-tazobactam (PTZ) is a broad-spectrum β-lactam antibiotic, frequently used for pulmonary infections. Lung antibiotic concentration reflects target site concentrations in patients with pneumonia. Critically ill patient’s exhibit marked pharmacokinetic (PK) variability. PTZ exposures resulting in maximal bacterial killing and prevention of emergence of drug resistance are not known. Administration of PTZ by extended infusions (EI) or using Bayesian dosage optimisation, instead of a fixed bolus regimen, may improve clinical outcomes. Experimental work was conducted in an in vitro hollow fibre infection model (HFIM) using two densities of Pseudomonas aeruginosa. Experimental data was described by a mathematical model allowing identification of PTZ exposures associated with bacterial killing and suppression of the emergence of resistance. The population PK of PTZ in the plasma and lung of 17 critically ill patients was estimated. Monte Carlo simulation was used to explore the proportion of patients that achieve the plasma and lung PTZ exposures associated with bacterial killing and resistance suppression and to determine the effect of administration schedule. Finally, the population PK of PTZ in the plasma of 146 critically ill patients was estimated and used to construct computer software that can individualise PTZ dosing. Precision of the dosing software was assessed in 8 additional individuals. At low bacterial density a trough piperacillin:MIC ratio of 3.4 for bolus and 10.4 for EI regimens were able to suppress the emergence of resistance. At higher bacterial density all regimens were associated with growth of a resistant sub-population. Pulmonary piperacillin and tazobactam concentrations were unpredictable and negatively correlated to pulmonary permeability. Simulations revealed that EI, compared with bolus dosing, of PTZ is associated with a higher likelihood of bacteria killing. Similar probability of developing resistance was predicted with PTZ administration by EI and by bolus administration. Performance of the dose optimisation software was satisfactory.Current PTZ regimens are insufficient to treat pneumonia in approximately 14% of critically ill patients. Delivery of PTZ by EI may be a more effective method of administration for some patients with nosocomial infections. Individualised PTZ regimens, delivering a target piperacillin concentration, identified in a HFIM, are achievable and should improved clinical outcomes. Patients with a high bacterial burden may required alternative therapeutic strategies to maximize bacterial killing and prevent antimicrobial resistance.

Pneumonia is a frequently fatal disease affecting patients in intensive care units. These patients are commonly treated with piperacillin-tazobactam, a broad spectrum antibiotic that is extensively used in the NHS. Currently all critically ill patients (except those in renal failure) are…

Advisors/Committee Members: Denning, David.

Subjects/Keywords: Pharmacokinetics; Pharmacodynamics; Piperacillin-tazobactam

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Felton, T. (2014). Antimicrobial therapy in critically ill patients: Improving clinical outcomes using a translational pharmacological approach. (Doctoral Dissertation). University of Manchester. Retrieved from http://www.manchester.ac.uk/escholar/uk-ac-man-scw:235681

Chicago Manual of Style (16^th Edition):

Felton, Timothy. “Antimicrobial therapy in critically ill patients: Improving clinical outcomes using a translational pharmacological approach.” 2014. Doctoral Dissertation, University of Manchester. Accessed February 27, 2021. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:235681.

MLA Handbook (7^th Edition):

Felton, Timothy. “Antimicrobial therapy in critically ill patients: Improving clinical outcomes using a translational pharmacological approach.” 2014. Web. 27 Feb 2021.

Vancouver:

Felton T. Antimicrobial therapy in critically ill patients: Improving clinical outcomes using a translational pharmacological approach. [Internet] [Doctoral dissertation]. University of Manchester; 2014. [cited 2021 Feb 27]. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:235681.

Council of Science Editors:

Felton T. Antimicrobial therapy in critically ill patients: Improving clinical outcomes using a translational pharmacological approach. [Doctoral Dissertation]. University of Manchester; 2014. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:235681

University of Adelaide

3. Licari, Giovanni. The stereoselective pharmacodynamics of the enantiomers of perhexiline.

Degree: 2013, University of Adelaide

URL: http://hdl.handle.net/2440/84991

► In the past decade there has been growing interest and evidence that altered myocardial energy metabolism plays a major role in the onset and/or progression… (more)

▼ In the past decade there has been growing interest and evidence that altered myocardial energy metabolism plays a major role in the onset and/or progression of ischaemic heart disease and heart failure. The anti-anginal agent perhexiline, marketed in Australia as 50:50 racemic mixture of (+)- and (-)-enantiomers, was one of the original metabolic agents introduced for clinical use in the 1970’s. Its mechanism of action is thought to involve manipulation of cellular energetics by inhibiting fatty acid metabolism through its interaction with the carnitine palmitoyltransferase system. This allows for a ‘switch’ in energy towards utilisation of carbohydrates, resulting in a greater net production of ATP per unit of oxygen used. However, perhexiline has a narrow therapeutic index. Hence clinical usage requires careful dosage individualisation using therapeutic drug monitoring in order to minimise adverse effects such as peripheral neuropathy and hepatotoxicity associated with elevated plasma perhexiline concentrations. There are currently no studies investigating the toxicity and efficacy of the individual enantiomers of perhexiline in vivo and my aim was to address this considerable gap in knowledge. Study 1: This study investigated the effects of (+) and (-)-perhexiline on superoxide formation by NADPH oxidase in intact neutrophils from healthy subjects and patients with symptomatic stable angina pectoris. (-)-Perhexiline showed a greater inhibition of superoxide formation than (+)-perhexiline (P<0.05, Wilcoxon matched paired test) in neutrophils from 11 healthy volunteers, with median IC50 values of 1.19 and 1.64μM, respectively. In 6 patients with angina, neutrophil superoxide formation was also significantly inhibited by both (+)- and (-)-perhexiline with IC50 values of 2.07μM (1.04-2.95μM) and 1.35μM (1.08-1.86μM) respectively; however there was no significant difference between the two enantiomers. This study demonstrates that both enantiomers dose dependently inhibit superoxide formation by neutrophil NADPH oxidase and are both likely to contribute to the beneficial anti-oxidant properties of perhexiline. Study 2: This study compared female Dark Agouti (DA) and Sprague Dawley (SD) rats, as models of CYP2D6 metabolism and hepatotoxicity after administration of perhexiline. Median (range) perhexiline concentrations in liver and plasma of the SD strain (n=4) were 5.42 (0.92 – 8.22) μg/g and 0.09 (0.04 – 0.13) mg/L, respectively. The DA strain (n=4) showed higher plasma (0.50 (0.16 – 1.13) mg/L, P<0.05) and liver (24.47 (9.40 – 54.70) μg/g, P<0.05) perhexiline concentrations, and cis-OH-perhexiline concentrations in plasma and liver of DA rats were 2.5 and 3.7 fold higher compared to SD rats. In both strains the plasma concentration ratio of (+):(-) enantiomers was approximately 2:1.When compared to their controls, DA rats treated with perhexiline had significantly higher plasma LDH concentrations (2-fold, P<0.05), whilst there were no changes in biochemical liver function tests in the SD group. Study 3: The aim of… Advisors/Committee Members: Sallustio, Benedetta Cristina (advisor), Somogyi, Andrew Alexander (advisor), School of Medical Sciences (school).

Subjects/Keywords: stereoselective; pharmacodynamics; enantiomers; perhexiline

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Licari, G. (2013). The stereoselective pharmacodynamics of the enantiomers of perhexiline. (Thesis). University of Adelaide. Retrieved from http://hdl.handle.net/2440/84991

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Licari, Giovanni. “The stereoselective pharmacodynamics of the enantiomers of perhexiline.” 2013. Thesis, University of Adelaide. Accessed February 27, 2021. http://hdl.handle.net/2440/84991.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Licari, Giovanni. “The stereoselective pharmacodynamics of the enantiomers of perhexiline.” 2013. Web. 27 Feb 2021.

Vancouver:

Licari G. The stereoselective pharmacodynamics of the enantiomers of perhexiline. [Internet] [Thesis]. University of Adelaide; 2013. [cited 2021 Feb 27]. Available from: http://hdl.handle.net/2440/84991.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Licari G. The stereoselective pharmacodynamics of the enantiomers of perhexiline. [Thesis]. University of Adelaide; 2013. Available from: http://hdl.handle.net/2440/84991

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Harvard University

4. Tanudra, Maria. Leveraging the Dynamic in Vitro Hollow Fiber Infection Model in Determining Optimal Clinical Dose of β-Lactam and β-Lactamase Inhibitor Combinations.

Degree: ALM, 2018, Harvard University

URL: http://nrs.harvard.edu/urn-3:HUL.InstRepos:42004045

►

Infectious disease is one of the top ten leading causes of death worldwide (WHO, 2017). Emergence of new mechanisms of antibiotic resistance continually rises and… (more)

Subjects/Keywords: Hollow Fiber System; Pharmacokinetics/Pharmacodynamics

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Tanudra, M. (2018). Leveraging the Dynamic in Vitro Hollow Fiber Infection Model in Determining Optimal Clinical Dose of β-Lactam and β-Lactamase Inhibitor Combinations. (Masters Thesis). Harvard University. Retrieved from http://nrs.harvard.edu/urn-3:HUL.InstRepos:42004045

Chicago Manual of Style (16^th Edition):

Tanudra, Maria. “Leveraging the Dynamic in Vitro Hollow Fiber Infection Model in Determining Optimal Clinical Dose of β-Lactam and β-Lactamase Inhibitor Combinations.” 2018. Masters Thesis, Harvard University. Accessed February 27, 2021. http://nrs.harvard.edu/urn-3:HUL.InstRepos:42004045.

MLA Handbook (7^th Edition):

Tanudra, Maria. “Leveraging the Dynamic in Vitro Hollow Fiber Infection Model in Determining Optimal Clinical Dose of β-Lactam and β-Lactamase Inhibitor Combinations.” 2018. Web. 27 Feb 2021.

Vancouver:

Tanudra M. Leveraging the Dynamic in Vitro Hollow Fiber Infection Model in Determining Optimal Clinical Dose of β-Lactam and β-Lactamase Inhibitor Combinations. [Internet] [Masters thesis]. Harvard University; 2018. [cited 2021 Feb 27]. Available from: http://nrs.harvard.edu/urn-3:HUL.InstRepos:42004045.

Council of Science Editors:

Tanudra M. Leveraging the Dynamic in Vitro Hollow Fiber Infection Model in Determining Optimal Clinical Dose of β-Lactam and β-Lactamase Inhibitor Combinations. [Masters Thesis]. Harvard University; 2018. Available from: http://nrs.harvard.edu/urn-3:HUL.InstRepos:42004045

University of Manchester

5. Felton, Timothy. Antimicrobial therapy in critically ill patients : improving clinical outcomes using a translational pharmacological approach.

Degree: PhD, 2014, University of Manchester

URL: https://www.research.manchester.ac.uk/portal/en/theses/antimicrobial-therapy-in-critically-ill-patients-improving-clinical-outcomes-using-a-translational-pharmacological-approach(afffd886-c447-4974-ab0b-a9e8a8c8f2b2).html ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.626967

► Pulmonary infections in critically ill patients are common, frequently lethal and treatment may be complicated by bacterial resistance. Piperacillin-tazobactam (PTZ) is a broad-spectrum β-lactam antibiotic,… (more)

▼ Pulmonary infections in critically ill patients are common, frequently lethal and treatment may be complicated by bacterial resistance. Piperacillin-tazobactam (PTZ) is a broad-spectrum β-lactam antibiotic, frequently used for pulmonary infections. Lung antibiotic concentration reflects target site concentrations in patients with pneumonia. Critically ill patient’s exhibit marked pharmacokinetic (PK) variability. PTZ exposures resulting in maximal bacterial killing and prevention of emergence of drug resistance are not known. Administration of PTZ by extended infusions (EI) or using Bayesian dosage optimisation, instead of a fixed bolus regimen, may improve clinical outcomes. Experimental work was conducted in an in vitro hollow fibre infection model (HFIM) using two densities of Pseudomonas aeruginosa. Experimental data was described by a mathematical model allowing identification of PTZ exposures associated with bacterial killing and suppression of the emergence of resistance. The population PK of PTZ in the plasma and lung of 17 critically ill patients was estimated. Monte Carlo simulation was used to explore the proportion of patients that achieve the plasma and lung PTZ exposures associated with bacterial killing and resistance suppression and to determine the effect of administration schedule. Finally, the population PK of PTZ in the plasma of 146 critically ill patients was estimated and used to construct computer software that can individualise PTZ dosing. Precision of the dosing software was assessed in 8 additional individuals. At low bacterial density a trough piperacillin:MIC ratio of 3.4 for bolus and 10.4 for EI regimens were able to suppress the emergence of resistance. At higher bacterial density all regimens were associated with growth of a resistant sub-population. Pulmonary piperacillin and tazobactam concentrations were unpredictable and negatively correlated to pulmonary permeability. Simulations revealed that EI, compared with bolus dosing, of PTZ is associated with a higher likelihood of bacteria killing. Similar probability of developing resistance was predicted with PTZ administration by EI and by bolus administration. Performance of the dose optimisation software was satisfactory. Current PTZ regimens are insufficient to treat pneumonia in approximately 14% of critically ill patients. Delivery of PTZ by EI may be a more effective method of administration for some patients with nosocomial infections. Individualised PTZ regimens, delivering a target piperacillin concentration, identified in a HFIM, are achievable and should improved clinical outcomes. Patients with a high bacterial burden may required alternative therapeutic strategies to maximize bacterial killing and prevent antimicrobial resistance.

Subjects/Keywords: 615.1; Pharmacokinetics; Pharmacodynamics; Piperacillin-tazobactam

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Felton, T. (2014). Antimicrobial therapy in critically ill patients : improving clinical outcomes using a translational pharmacological approach. (Doctoral Dissertation). University of Manchester. Retrieved from https://www.research.manchester.ac.uk/portal/en/theses/antimicrobial-therapy-in-critically-ill-patients-improving-clinical-outcomes-using-a-translational-pharmacological-approach(afffd886-c447-4974-ab0b-a9e8a8c8f2b2).html ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.626967

Chicago Manual of Style (16^th Edition):

Felton, Timothy. “Antimicrobial therapy in critically ill patients : improving clinical outcomes using a translational pharmacological approach.” 2014. Doctoral Dissertation, University of Manchester. Accessed February 27, 2021. https://www.research.manchester.ac.uk/portal/en/theses/antimicrobial-therapy-in-critically-ill-patients-improving-clinical-outcomes-using-a-translational-pharmacological-approach(afffd886-c447-4974-ab0b-a9e8a8c8f2b2).html ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.626967.

MLA Handbook (7^th Edition):

Felton, Timothy. “Antimicrobial therapy in critically ill patients : improving clinical outcomes using a translational pharmacological approach.” 2014. Web. 27 Feb 2021.

Vancouver:

Felton T. Antimicrobial therapy in critically ill patients : improving clinical outcomes using a translational pharmacological approach. [Internet] [Doctoral dissertation]. University of Manchester; 2014. [cited 2021 Feb 27]. Available from: https://www.research.manchester.ac.uk/portal/en/theses/antimicrobial-therapy-in-critically-ill-patients-improving-clinical-outcomes-using-a-translational-pharmacological-approach(afffd886-c447-4974-ab0b-a9e8a8c8f2b2).html ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.626967.

Council of Science Editors:

Felton T. Antimicrobial therapy in critically ill patients : improving clinical outcomes using a translational pharmacological approach. [Doctoral Dissertation]. University of Manchester; 2014. Available from: https://www.research.manchester.ac.uk/portal/en/theses/antimicrobial-therapy-in-critically-ill-patients-improving-clinical-outcomes-using-a-translational-pharmacological-approach(afffd886-c447-4974-ab0b-a9e8a8c8f2b2).html ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.626967

University of Manchester

6. Jeans, Adam Rupert. The pharmacodynamics of antifungal agents against Aspergillus.

Degree: Thesis (M.D.), 2013, University of Manchester

URL: https://www.research.manchester.ac.uk/portal/en/theses/the-pharmacodynamics-of-antifungal-agents-against-aspergillus(42f0da51-46dc-4960-9912-d47e7871f496).html ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607018

► Background: Voriconazole is a first line agent for the treatment for invasive pulmonary aspergillosis. There are increasing reports of Aspergillus fumigatus isolates with reduced susceptibility… (more)

▼ Background: Voriconazole is a first line agent for the treatment for invasive pulmonary aspergillosis. There are increasing reports of Aspergillus fumigatus isolates with reduced susceptibility to voriconazole. I investigated the pharmacodynamics of voriconazole against drug susceptible and drug resistant strains of Aspergillus fumigatus through the development of a novel dynamic in vitro model of the human alveolus. I then investigated whether combination therapy with voriconazole and anidulafungin would be beneficial in the treatment of infection with these isolates. Methods: An in vitro dynamic model of IPA was developed that enabled simulation of human-like voriconazole pharmacokinetics. Galactomannan was used as a biomarker. The pharmacodynamics of voriconazole against wild-type and three resistant strains of A. fumigatus were defined. The results were bridged to humans to provide decision support for setting breakpoints for voriconazole using Clinical Laboratory Standards Institute (CLSI) and European Committee of Antimicrobial Susceptibility Testing (EUCAST) methodology. The interaction of voriconazole and anidulafungin in an in vitro static model was described using the Greco model. Results: Isolates with higher MICs required higher area under the concentration time curve (AUCs) to achieve suppression of galactomannan. An AUC:MIC using CLSI and EUCAST methodology that achieved suppression of galactomannan was 55 and 32.1, respectively. A trough concentration:MIC using CLSI and EUCAST methodology that achieved suppression of galactomannan was 1.68 and 1, respectively. Potential CLSI breakpoints for voriconazole are: susceptible ≤ 0.5 mg/L; resistant > 1 mg/L. Potential EUCAST breakpoints for voriconazole are: susceptible ≤ 1 mg/L; resistant > 2 mg/L. Galactomannan concentrations were only marginally reduced by anidulafungin monotherapy in the static model. An additive effect between voriconazole and anidulafungin was apparent. Conclusions: Voriconazole resistance mechanisms can be overcome with higher drug exposures, but this may require concentrations likely to cause toxicity in humans. The addition of anidulafungin does not markedly alter the exposure-response relationship of voriconazole. A rise in serum galactomannan during combination therapy with voriconazole and anidulafungin should be interpreted as treatment failure and not attributed to a paradoxical reaction related to echinocandin treatment. The dynamic in vitro model is a useful tool to address many remaining questions related to treatment of invasive fungal infection.

Subjects/Keywords: 615.7; Aspergillus; Pharmacodynamics; Voriconazole; Anidulafungin

Record Details Similar Records Cite « Share

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Jeans, A. R. (2013). The pharmacodynamics of antifungal agents against Aspergillus. (Doctoral Dissertation). University of Manchester. Retrieved from https://www.research.manchester.ac.uk/portal/en/theses/the-pharmacodynamics-of-antifungal-agents-against-aspergillus(42f0da51-46dc-4960-9912-d47e7871f496).html ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607018

Chicago Manual of Style (16^th Edition):

Jeans, Adam Rupert. “The pharmacodynamics of antifungal agents against Aspergillus.” 2013. Doctoral Dissertation, University of Manchester. Accessed February 27, 2021. https://www.research.manchester.ac.uk/portal/en/theses/the-pharmacodynamics-of-antifungal-agents-against-aspergillus(42f0da51-46dc-4960-9912-d47e7871f496).html ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607018.

MLA Handbook (7^th Edition):

Jeans, Adam Rupert. “The pharmacodynamics of antifungal agents against Aspergillus.” 2013. Web. 27 Feb 2021.

Vancouver:

Jeans AR. The pharmacodynamics of antifungal agents against Aspergillus. [Internet] [Doctoral dissertation]. University of Manchester; 2013. [cited 2021 Feb 27]. Available from: https://www.research.manchester.ac.uk/portal/en/theses/the-pharmacodynamics-of-antifungal-agents-against-aspergillus(42f0da51-46dc-4960-9912-d47e7871f496).html ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607018.

Council of Science Editors:

Jeans AR. The pharmacodynamics of antifungal agents against Aspergillus. [Doctoral Dissertation]. University of Manchester; 2013. Available from: https://www.research.manchester.ac.uk/portal/en/theses/the-pharmacodynamics-of-antifungal-agents-against-aspergillus(42f0da51-46dc-4960-9912-d47e7871f496).html ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607018

University of Gothenburg / Göteborgs Universitet

7. Henning, Matts, 1936-. Studies on the mode of action of î-methyldopa.

Degree: 1969, University of Gothenburg / Göteborgs Universitet

URL: http://hdl.handle.net/2077/11600

Subjects/Keywords: Methyldopa: pharmacodynamics

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Henning, Matts, 1. (1969). Studies on the mode of action of î-methyldopa. (Thesis). University of Gothenburg / Göteborgs Universitet. Retrieved from http://hdl.handle.net/2077/11600

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Henning, Matts, 1936-. “Studies on the mode of action of î-methyldopa.” 1969. Thesis, University of Gothenburg / Göteborgs Universitet. Accessed February 27, 2021. http://hdl.handle.net/2077/11600.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Henning, Matts, 1936-. “Studies on the mode of action of î-methyldopa.” 1969. Web. 27 Feb 2021.

Vancouver:

Henning, Matts 1. Studies on the mode of action of î-methyldopa. [Internet] [Thesis]. University of Gothenburg / Göteborgs Universitet; 1969. [cited 2021 Feb 27]. Available from: http://hdl.handle.net/2077/11600.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Henning, Matts 1. Studies on the mode of action of î-methyldopa. [Thesis]. University of Gothenburg / Göteborgs Universitet; 1969. Available from: http://hdl.handle.net/2077/11600

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Melbourne

8. Gwee, Amanda. Vancomycin pharmacokinetics and pharmacodynamics in young infants.

Degree: 2018, University of Melbourne

URL: http://hdl.handle.net/11343/221681

► Vancomycin is a glycopeptide antibiotic commonly used for the treatment of late-onset sepsis in young infants. Vancomycin dosing is challenging in young infants due to… (more)

▼ Vancomycin is a glycopeptide antibiotic commonly used for the treatment of late-onset sepsis in young infants. Vancomycin dosing is challenging in young infants due to the rapid physiological changes that occur after birth which effect both vancomycin disposition and clearance. Vancomycin is routinely administered to young infants as intermittent infusions (IIV) but studies show that current recommended IIV dosing regimens in paediatric drug formularies lead to subtherapeutic vancomycin levels in the majority of young infants. Therefore, in some neonatal units, continuous infusions of vancomycin (CIV) are used routinely based on data from adult studies that suggest CIV is associated with improved attainment of target concentrations and fewer drug side effects. Therapeutic drug monitoring of vancomycin is used to determine both treatment efficacy as well as toxicity. Current recommendations for target trough concentrations of 10 to 20 mg/L are based on the pharmacodynamic target (relationship between drug concentration and drug effect) for Staphylococcus aureus. However, there are limited data on the pharmacodynamic target for other staphylococci, in particular coagulase-negative staphylococci that are also important pathogens in young infants. My PhD aims to optimise vancomycin dosing in young infants, as well as to study the pharmacodynamics of vancomycin in vitro to improve the treatment of late-onset infections in young infants. The first section of this thesis focuses on determining the optimal vancomycin dosing regimen in young infants. From my literature review on CIV dosing in young infants (see Appendix 1) the existing data suggest that CIV is well tolerated and achieves target vancomycin levels in the majority of study participants. Therefore, to evaluate CIV compared to IIV (the current standard of care), chapters 3 and 4 of my thesis comprise: (i) a protocol for a multicentre randomised controlled trial (RCT) of CIV compared to IIV in young infants aged 0 to 90 days (ii) the results of this RCT in 111 young infants in the neonatal intensive care setting. The second section of this thesis (chapter 5) describes an in vitro study designed to determine the in vitro pharmacodynamics of vancomycin for one of the most common coagulase-negative staphylococci causing late-onset sepsis in young infants, S. epidermidis. To guide recommendations for target vancomycin levels, this study determined whether vancomycin exhibits time- or concentration-dependent killing of S. epidermidis. The final section of my thesis (chapter 6) focuses on the development of a population pharmacokinetic model for vancomycin in young infants using non-linear mixed-effects modelling (NONMEM). The model is based on data from the RCT (chapter 4). Using this model, the relationship between trough concentrations and the area under the concentration-time curve over a 24-hour period (AUC24) were determined as well as whether vancomycin therapeutic drug monitoring (TDM) can be done earlier during treatment.

Subjects/Keywords: vancomycin; glycopeptide; pharmacokinetics; pharmacodynamics; Staphylococcus

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Gwee, A. (2018). Vancomycin pharmacokinetics and pharmacodynamics in young infants. (Doctoral Dissertation). University of Melbourne. Retrieved from http://hdl.handle.net/11343/221681

Chicago Manual of Style (16^th Edition):

Gwee, Amanda. “Vancomycin pharmacokinetics and pharmacodynamics in young infants.” 2018. Doctoral Dissertation, University of Melbourne. Accessed February 27, 2021. http://hdl.handle.net/11343/221681.

MLA Handbook (7^th Edition):

Gwee, Amanda. “Vancomycin pharmacokinetics and pharmacodynamics in young infants.” 2018. Web. 27 Feb 2021.

Vancouver:

Gwee A. Vancomycin pharmacokinetics and pharmacodynamics in young infants. [Internet] [Doctoral dissertation]. University of Melbourne; 2018. [cited 2021 Feb 27]. Available from: http://hdl.handle.net/11343/221681.

Council of Science Editors:

Gwee A. Vancomycin pharmacokinetics and pharmacodynamics in young infants. [Doctoral Dissertation]. University of Melbourne; 2018. Available from: http://hdl.handle.net/11343/221681

University of Manitoba

9. Calic, Divna. A pharmacokinetic/pharmacodynamic evaluation of cefazolin antimicrobial prophylaxis in cardiac surgery with cardiopulmonary bypass.

Degree: Pharmacy, 2020, University of Manitoba

URL: http://hdl.handle.net/1993/34632

► Surgical site infections (SSI) following cardiac surgery result in significant patient morbidity and mortality. Antimicrobial prophylaxis (AP) with cefazolin is a core strategy for preventing… (more)

▼ Surgical site infections (SSI) following cardiac surgery result in significant patient morbidity and mortality. Antimicrobial prophylaxis (AP) with cefazolin is a core strategy for preventing SSI. This was the first pharmacokinetic-pharmacodynamic study of guideline-recommended cefazolin AP in cardiac surgery with cardiopulmonary bypass (CPB). In this non-interventional study, subjects (n = 55, 65 ± 10 years, 80 ± 19 mL/min/72kg) undergoing cardiac surgery received cefazolin AP and had blood samples collected at relevant times intraoperatively. Total and free cefazolin concentrations were measured by LC-MS/MS. Subjects were monitored for SSI during and after hospitalization. Total cefazolin concentrations at wound closure were compared to target concentrations ≥ 40 mg/L and risk factors for below-target concentrations identified. Free cefazolin concentrations were used to characterize cefazolin protein binding (PB). A population-pharmacokinetic model was constructed to characterize the pharmacokinetics of cefazolin during cardiac surgery. Finally, a pharmacodynamic analysis was conducted to investigate the relationship between cefazolin concentrations and SSI development. Almost 10% of cefazolin concentrations at wound closure were < 40 mg/L. Shorter surgery duration, lower body weight and lower total cefazolin dose per hour of surgery were independently associated with below-target concentrations. A significant dose threshold of 7.6 mg/kgDW/h was identified and used to optimize the AP regimen, which demonstrated the inadequacy of 1-gram doses. The PB of cefazolin during surgery was 72 ± 8% compared to the usual 80%. PB saturation was observed during/post-CPB. The elimination rate constant was similar (0.35 ± 0.07 h-1), while the volume of distribution was higher (0.14 ± 0.05 L/kg) during cardiac surgery with CPB versus healthy volunteers. In the PD analysis, longer duration of surgery and lower total cefazolin closure concentrations were independently associated with SSI. Significant increases in risk of SSI were identified at thresholds of surgery duration > 5.8 hours and total closure concentrations < 104 mg/L. Most importantly, the findings of this study were translated to clinical practice. An AP regimen designed to achieve target closure concentrations during cardiac surgery with CPB has been adopted where cefazolin AP consists of 2 grams (3 grams if ≥120 kg) preoperatively and re-dosed every 3 hours intraoperatively, with adjustments for renal function. Advisors/Committee Members: Zelenitsky, Sheryl (Pharmacy) (supervisor), Ariano, Robert ( Pharmacy) (examiningcommittee), Lakowski, Ted (Pharmacy) (examiningcommittee), Grocott, Hilary (Surgery) (examiningcommittee), Shwarz, Stephan (University of British Columbia) (examiningcommittee).

Subjects/Keywords: Pharmacokinetics; Pharmacodynamics; Cefazolin; Cardiac surgery

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APA (6^th Edition):

Calic, D. (2020). A pharmacokinetic/pharmacodynamic evaluation of cefazolin antimicrobial prophylaxis in cardiac surgery with cardiopulmonary bypass. (Thesis). University of Manitoba. Retrieved from http://hdl.handle.net/1993/34632

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Calic, Divna. “A pharmacokinetic/pharmacodynamic evaluation of cefazolin antimicrobial prophylaxis in cardiac surgery with cardiopulmonary bypass.” 2020. Thesis, University of Manitoba. Accessed February 27, 2021. http://hdl.handle.net/1993/34632.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Calic, Divna. “A pharmacokinetic/pharmacodynamic evaluation of cefazolin antimicrobial prophylaxis in cardiac surgery with cardiopulmonary bypass.” 2020. Web. 27 Feb 2021.

Vancouver:

Calic D. A pharmacokinetic/pharmacodynamic evaluation of cefazolin antimicrobial prophylaxis in cardiac surgery with cardiopulmonary bypass. [Internet] [Thesis]. University of Manitoba; 2020. [cited 2021 Feb 27]. Available from: http://hdl.handle.net/1993/34632.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Calic D. A pharmacokinetic/pharmacodynamic evaluation of cefazolin antimicrobial prophylaxis in cardiac surgery with cardiopulmonary bypass. [Thesis]. University of Manitoba; 2020. Available from: http://hdl.handle.net/1993/34632

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Universiteit Utrecht

10. Keizer, R.J. Pharmacometrics in early clinical drug development.

Degree: 2010, Universiteit Utrecht

URL: http://dspace.library.uu.nl:8080/handle/1874/179786

► Pharmacometrics, the science of quantitative clinical pharmacology, has been recognized as one of the main research fields able to improve efficiency in drug development, and… (more)

▼ Pharmacometrics, the science of quantitative clinical pharmacology, has been recognized as one of the main research fields able to improve efficiency in drug development, and to reduce attrition rates on the route from drug discovery to approval. This field of drug research, which builds heavily on the sciences of mathematics, statistics, pharmacology and biology, provides a tool for studying relationships between drug exposure and drug effects. This thesis concerns the application of pharmacometrics in the early clinical development of drugs, and has a strong focus on oncology. The thesis shows that the use of population modelling & simulation greatly facilitates the appropriate handling of all available data, including data which may be difficult to handle using standard approaches (e.g. missing, censored or baseline data). It is shown here that, especially when faced with such limitations or challenges, the use of modeling techniques instead of reliance on the more conventional statistical techniques, allows the most appropriate and data-efficient analysis of data. Of course, this is especially relevant when data is sparse or associated with high variability, which is often the case in (early) clinical studies. The thesis shows that the use of pharmacodynamic biomarkers in a PK-PD analysis can greatly support the early clinical development of new drugs. Several pharmacokinetic-pharmacodynamic (PK-PD) analyses in early drug development are presented in the thesis, incorporating a PD biomarker for efficacy or toxicity. One of the chapters presents the construction of a model for the occurrence of hypertension and proteinuria toxicity during treatment with a novel anticancer drug, based on early clinical data. Subsequent simulations using this model provided support for the hypertension intervention scheme proposed for Phase II clinical development, and showed that intra-patient dose escalations using hypertension as a biomarker may be feasible without inducing considerable toxicity. In another analysis, preclinical and early clinical biomarker and tumour growth data were combined to allow an early assessment of anticancer activity of another novel drug. In two other chapters, investigations into the predictive ability and schedule-dependency of a PK-PD model for haematological toxicity during treatment with anticancer drugs are described. When modelling early clinical or preclinical data, the modeller is often confronted with technical difficulties concerning incomplete data. In the final section of the thesis, investigations are presented into two such problems: data below the limit of quantification (BLOQ) and incomplete covariate datasets. For the former problem, it was shown that the use of extrapolated BLOQ concentration data provides superior performance over established methods. For the latter problem, an approach in which an extra parameter for covariate effect was estimated for the group in which data on the covariate was missing, provided the easiest and most robust performance to analyses such datasets.… Advisors/Committee Members: Schellens, J.H.M., Beijnen, J.H., Huitema, A.D.R..

Subjects/Keywords: Farmacie; pharmacometrics; pharmacokinetics; pharmacodynamics; pharmacodynamics; drug development; oncology; cancer

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Keizer, R. J. (2010). Pharmacometrics in early clinical drug development. (Doctoral Dissertation). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/179786

Chicago Manual of Style (16^th Edition):

Keizer, R J. “Pharmacometrics in early clinical drug development.” 2010. Doctoral Dissertation, Universiteit Utrecht. Accessed February 27, 2021. http://dspace.library.uu.nl:8080/handle/1874/179786.

MLA Handbook (7^th Edition):

Keizer, R J. “Pharmacometrics in early clinical drug development.” 2010. Web. 27 Feb 2021.

Vancouver:

Keizer RJ. Pharmacometrics in early clinical drug development. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2010. [cited 2021 Feb 27]. Available from: http://dspace.library.uu.nl:8080/handle/1874/179786.

Council of Science Editors:

Keizer RJ. Pharmacometrics in early clinical drug development. [Doctoral Dissertation]. Universiteit Utrecht; 2010. Available from: http://dspace.library.uu.nl:8080/handle/1874/179786

University of Otago

11. Wright, Daniel Frank. Model-based Drug Dosing .

Degree: 2013, University of Otago

URL: http://hdl.handle.net/10523/4398

► The safe and effective use of medicines requires that prescribers use the right drug for the right patient at the right dose. The choice of… (more)

▼ The safe and effective use of medicines requires that prescribers use the right drug for the right patient at the right dose. The choice of dosing regimen requires a quantitative understanding of the magnitude of the drug effect for any given dose, the time course over which desired and adverse effects are expected to occur, and how variability between patients will impact dose requirements. The methods used by prescribers to achieve individualised dosing in practice are poorly understood and it is likely that a trial and error process prevails for many drugs. A model-based approach to drug dosing provides a means of predicting drug response in individual patients and, therefore, constitutes a useful tool for designing safe and effective dosing regimens in clinical practice. A model-based approach was explored for the dosing of warfarin, simvastatin and allopurinol. Each drug presented a different challenge in the clinical setting with regards to safe and effective dosing and this necessitated the use of different pharmacometric methodologies in each case. For warfarin, a Bayesian forecasting method for dose individualisation was developed. The method required the identification and evaluation of a suitable prior model and the development of a novel optimal International Normalised Ratio (INR) sampling design for Bayesian parameter control. The performance of this design was evaluated using simulation-estimation techniques. It was predicted that this method will result in a substantial improvement in INR control and time-in-the-therapeutic range compared to currently dosing methods. For simvastatin, a simulation based study using a published pharmacokinetic-pharmacodynamic model was conducted. This analysis addressed a clinical research question related to the practice of dosing simvastatin at bedtime. The model predicted that circadian low-density lipoprotein (LDL) production had a negligible impact on simvastatin effect and that dosing in the morning should be considered for patients who may be less compliant with bedtime dosing. For allopurinol, a novel population parent-metabolite model was developed. A covariate analysis found that renal function, fat free mass and diuretic use determined the differences in allopurinol and oxypurinol exposure between patients. This pharmacokinetic model provided the basis for an integrated PKPD model, intended to describe the effect of allopurinol on serum urate. While a suitable PD model could not be developed with the data available, optimal design methodologies were used to evaluate future study designs and alternative models for the allopurinol-urate effect. A PKPD model-based approach to inform rational drug dosing was successfully demonstrated for warfarin, simvastatin, and allopurinol. By quantifying the magnitude and time course of drug effects and by elucidating the patient characteristics which determine drug response between individuals, the model-based approach to drug dosing provides a useful tool to aid the safe and effective use of medicines in clinical… Advisors/Committee Members: Duffull, Stephen (advisor).

Subjects/Keywords: warfarin; simvastatin; allopurinol; pharmacokinetics; pharmacodynamics; modelling

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APA (6^th Edition):

Wright, D. F. (2013). Model-based Drug Dosing . (Doctoral Dissertation). University of Otago. Retrieved from http://hdl.handle.net/10523/4398

Chicago Manual of Style (16^th Edition):

Wright, Daniel Frank. “Model-based Drug Dosing .” 2013. Doctoral Dissertation, University of Otago. Accessed February 27, 2021. http://hdl.handle.net/10523/4398.

MLA Handbook (7^th Edition):

Wright, Daniel Frank. “Model-based Drug Dosing .” 2013. Web. 27 Feb 2021.

Vancouver:

Wright DF. Model-based Drug Dosing . [Internet] [Doctoral dissertation]. University of Otago; 2013. [cited 2021 Feb 27]. Available from: http://hdl.handle.net/10523/4398.

Council of Science Editors:

Wright DF. Model-based Drug Dosing . [Doctoral Dissertation]. University of Otago; 2013. Available from: http://hdl.handle.net/10523/4398

Mississippi State University

12. Riggs, Caitlin Nicole. Development of a pharmacodynamic assay to assess the effect of cyclosporine in the canine patient.

Degree: PhD, Veterinary Medicine, College of, 2017, Mississippi State University

URL: http://sun.library.msstate.edu/ETD-db/theses/available/etd-06162017-212341/ ;

► Cyclosporine is used in veterinary medicine to treat a number of inflammatory and immune-mediated conditions, however firm oral dosing protocols have yet to be… (more)

▼ Cyclosporine is used in veterinary medicine to treat a number of inflammatory and immune-mediated conditions, however firm oral dosing protocols have yet to be established in the dog. Traditionally a pharmacokinetic approach, through measurement of blood drug concentrations, has been the primary method of establishing if the given dose is effectively suppressing the immune system. However, there is some debate over how well blood drug concentrations correspond to immunosuppression, since individuals can vary in response to the same drug concentration. Our research group believes that a pharmacodynamic approach could alternatively be used to accurately determine cyclosporine dosages in individual patients since this will give a measurement of the immune systems response to the drug, rather than simply how the body is processing it. This method will give a more accurate assessment of the patients immune system, and allow for better immunosuppressant therapy. The objective of this thesis was to develop a quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay that could reliably predict patient outcome during cyclosporine treatment. This assay would essentially work as a diagnostic tool that clinicians can use to help determine if they were using an appropriate cyclosporine dose for their patients. The assay measures cytokine expression of activated T cells, which are the target cell for the active metabolite of cyclosporine. Our objectives were achieved, firstly, through validation of the assay. Since this assay will be used by clinicians throughout the nation, we first established if shipping conditions affected the sample, and therefore assay results. Once the effect of sample storage time and temperature were determined, optimal sample collection timing was established. Finally, cytokine levels were measured in samples from clinical cases and healthy control dogs to examine the difference in cytokine expression between these two groups. An effective and reliable treatment method for cyclosporine has yet to be established in the dog; therefore the results of this thesis will lead to better therapeutic monitoring and more efficient use of cyclosporine therapy in canine patients. Advisors/Committee Members: Camilo Bulla (committee member), Todd Pharr (committee member), Mark Lawrence (committee member), Todd Archer (chair), Andrew Mackin (chair).

Subjects/Keywords: qRT-PCR; pharmacodynamics; T cell; dog; cyclosporine

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APA (6^th Edition):

Riggs, C. N. (2017). Development of a pharmacodynamic assay to assess the effect of cyclosporine in the canine patient. (Doctoral Dissertation). Mississippi State University. Retrieved from http://sun.library.msstate.edu/ETD-db/theses/available/etd-06162017-212341/ ;

Chicago Manual of Style (16^th Edition):

Riggs, Caitlin Nicole. “Development of a pharmacodynamic assay to assess the effect of cyclosporine in the canine patient.” 2017. Doctoral Dissertation, Mississippi State University. Accessed February 27, 2021. http://sun.library.msstate.edu/ETD-db/theses/available/etd-06162017-212341/ ;.

MLA Handbook (7^th Edition):

Riggs, Caitlin Nicole. “Development of a pharmacodynamic assay to assess the effect of cyclosporine in the canine patient.” 2017. Web. 27 Feb 2021.

Vancouver:

Riggs CN. Development of a pharmacodynamic assay to assess the effect of cyclosporine in the canine patient. [Internet] [Doctoral dissertation]. Mississippi State University; 2017. [cited 2021 Feb 27]. Available from: http://sun.library.msstate.edu/ETD-db/theses/available/etd-06162017-212341/ ;.

Council of Science Editors:

Riggs CN. Development of a pharmacodynamic assay to assess the effect of cyclosporine in the canine patient. [Doctoral Dissertation]. Mississippi State University; 2017. Available from: http://sun.library.msstate.edu/ETD-db/theses/available/etd-06162017-212341/ ;

Temple University

13. Wang, Shining. DRUG DEVELOPMENT OF TARGETED ANTICANCER DRUGS BASED ON PK/PD INVESTIGATIONS.

Degree: PhD, 2008, Temple University

URL: http://digital.library.temple.edu/u?/p245801coll10,2535

►

Pharmaceutics

EGFR inhibitors, such as gefitinib, are examples of targeted anticancer drugs whose drug sensitivity is related to gene mutations that adds a pharmacogenetic [PG]… (more)

▼

Pharmaceutics

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…

Advisors/Committee Members: Gallo, James M., Krynetskiy, Evgeny, Nagar, Swati V., Johnson, Steven W..

Subjects/Keywords: Health Sciences, Pharmacy; pharmacokinetics; pharmacodynamics; gefitinib; glioblastoma

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APA (6^th Edition):

Wang, S. (2008). DRUG DEVELOPMENT OF TARGETED ANTICANCER DRUGS BASED ON PK/PD INVESTIGATIONS. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,2535

Chicago Manual of Style (16^th Edition):

Wang, Shining. “DRUG DEVELOPMENT OF TARGETED ANTICANCER DRUGS BASED ON PK/PD INVESTIGATIONS.” 2008. Doctoral Dissertation, Temple University. Accessed February 27, 2021. http://digital.library.temple.edu/u?/p245801coll10,2535.

MLA Handbook (7^th Edition):

Wang, Shining. “DRUG DEVELOPMENT OF TARGETED ANTICANCER DRUGS BASED ON PK/PD INVESTIGATIONS.” 2008. Web. 27 Feb 2021.

Vancouver:

Wang S. DRUG DEVELOPMENT OF TARGETED ANTICANCER DRUGS BASED ON PK/PD INVESTIGATIONS. [Internet] [Doctoral dissertation]. Temple University; 2008. [cited 2021 Feb 27]. Available from: http://digital.library.temple.edu/u?/p245801coll10,2535.

Council of Science Editors:

Wang S. DRUG DEVELOPMENT OF TARGETED ANTICANCER DRUGS BASED ON PK/PD INVESTIGATIONS. [Doctoral Dissertation]. Temple University; 2008. Available from: http://digital.library.temple.edu/u?/p245801coll10,2535

University of Southern California

14. Chen, Xiaoying. Linkers in transferrin fusion proteins: effects on pharmacokinetics and pharmacodynamics.

Degree: PhD, Pharmaceutical Sciences, 2011, University of Southern California

URL: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/637770/rec/3837

► Recombinant fusion proteins have become an important class of biomolecules since the invention of recombinant DNA technology. As an indispensable component of recombinant fusion proteins,… (more)

▼ Recombinant fusion proteins have become an important class of biomolecules since the invention of recombinant DNA technology. As an indispensable component of recombinant fusion proteins, linkers have shown increasing importance in the construction of stable, bioactive fusion proteins. In the development of recombinant transferrin (Tf)-fusion proteins for protein drug oral delivery, various linkers have been designed to improve the biological activity, or to achieve desired pharmacokinetic and pharmacodynamic properties. ❧ The Introduction in this dissertation first reviewed the mechanism for Tf receptor-mediated protein drug oral delivery, as well as the recombinant Tf-fusion proteins that have been constructed previously in our lab. It also covers the current knowledge of fusion protein linkers and summarizes examples for their applications. The basic function of linkers is to covalently join the functional domains in the fusion proteins. However, linkers can offer many other advantages for fusion proteins, such as controlled distance between domains, correct folding and confirmation, improved biological activity, increased expression yield, and functional domain separation in vivo. ❧ In order to achieve desired pharmacokinetic profiles and improved biological activity, an in vivo cleavable disulfide linker was designed for in vivo release of protein domains from recombinant Tf-fusion proteins. This novel disulfide linker, based on a cyclopeptide containing a thrombin-sensitive sequence and an intra-molecular disulfide bond, was inserted between Tf and granulocyte colony-stimulating factor (G-CSF)/growth hormone (GH). The fusion proteins linked via the reversible disulfide bond was able to quickly separate the protein domains in vivo upon the reduction of the disulfide bond. After released from the fusion protein, free G-CSF exhibited an improved biological activity in a cell proliferation assay. Due to the short plasma half-life of released free G-CSF, G-CSF-Tf fusion protein with the disulfide linker did not exhibit improved in vivo biological activity compared to its counterpart with a stable peptide linker. This linker design can be adapted to diverse recombinant fusion proteins where in vivo separation of protein domains is required to achieve improved therapeutic effect, desirable pharmacokinetic profile and biodistribution of the functional domains. ❧ Next, recombinant fusion proteins consisting of Tf and GH/G-CSF were constructed as a model for studying the pharmacokinetics (PK) of bifunctional fusion proteins. The impact of linkers on the PK of bifunctional fusion proteins was investigated through the insertion of 3 linkers between the functional domains. The results showed that the insertion of different linkers between the two protein domains altered the binding affinities of the fusion proteins to both domain receptors, and that the fusion proteins’ plasma half-lives were greatly affected. A strong correlation between GH receptor binding affinity and plasma half-life of GH-Tf fusion proteins was… Advisors/Committee Members: Shen, Wei-Chiang (Committee Chair), Ou, James (Committee Member), Okamoto, Curtis Toshio (Committee Member), Haworth, Ian S. (Committee Member), Stiles, Bangyan L. (Committee Member).

Subjects/Keywords: linker; fusion protein; transferrin; pharmacokinetics; pharmacodynamics

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Chen, X. (2011). Linkers in transferrin fusion proteins: effects on pharmacokinetics and pharmacodynamics. (Doctoral Dissertation). University of Southern California. Retrieved from http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/637770/rec/3837

Chicago Manual of Style (16^th Edition):

Chen, Xiaoying. “Linkers in transferrin fusion proteins: effects on pharmacokinetics and pharmacodynamics.” 2011. Doctoral Dissertation, University of Southern California. Accessed February 27, 2021. http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/637770/rec/3837.

MLA Handbook (7^th Edition):

Chen, Xiaoying. “Linkers in transferrin fusion proteins: effects on pharmacokinetics and pharmacodynamics.” 2011. Web. 27 Feb 2021.

Vancouver:

Chen X. Linkers in transferrin fusion proteins: effects on pharmacokinetics and pharmacodynamics. [Internet] [Doctoral dissertation]. University of Southern California; 2011. [cited 2021 Feb 27]. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/637770/rec/3837.

Council of Science Editors:

Chen X. Linkers in transferrin fusion proteins: effects on pharmacokinetics and pharmacodynamics. [Doctoral Dissertation]. University of Southern California; 2011. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/637770/rec/3837

University of Sydney

15. Kim, Hannah Yejin. Personalised Medicine in the Treatment of Cancer .

Degree: 2018, University of Sydney

URL: http://hdl.handle.net/2123/20103

► Understanding of pharmacokinetic-pharmacodynamic relationship for a given drug, and factors determining this, is an important part of personalised medicine in terms of choosing the correct… (more)

▼ Understanding of pharmacokinetic-pharmacodynamic relationship for a given drug, and factors determining this, is an important part of personalised medicine in terms of choosing the correct regimen and maximising the therapeutic benefit with minimal toxicity. In the field of cancer, diversity of disease characteristics, complexity of regimens, as well as limited understanding of PK-PD profiles of rapidly-progressing anticancer drugs, create challenges for clinicians and patients to achieve the optimal outcome. This thesis addresses areas of cancer treatment where there is a need for identification of pharmacokinetic (PK), pharmacogenetic (PG) or physiological contributors, which may explain the observed variability, pharmacokinetics or toxicity of the studied drugs. The first component of the work aimed to investigate pharmacogenetic factors determining pharmacokinetics of actinomycin D. The study involves identification of the candidate transporters through in vitro uptake assays, which then led to clinical PK-PG analysis to determine clinically-significant transporter genotype influencing actinomycin D pharmacokinetics. The second component of the work explores pharmacodynamic associations between toxicity (pyrexia: body temperature > 38C) and exposure to dabrafenib and trametinib (CombiDT) used in the treatment of patients with melanoma expressing the common BRAF V600E/K mutation. A biomarker analysis using a panel of cytokines was also conducted to investigate their role in predicting or indicating the incidence of this toxicity. The significant findings of our study include identification of involvement of Solute Carrier (SLC) transporters (OAT4 and PEPT2) in actinomycin D uptake in vitro and the potentially predictive role of cytokines (IL-1B and IL-6) in CombiDT-induced pyrexia. Some of the results, such as the role of SLC transporters in clinical pharmacokinetics of actinomycin D in paediatric cancer patients, and drug exposure-pyrexia relationship for CombiDT treatment, lacked definitive conclusions due to study limitations, and provide areas of further research. Overall, we believe that our study has made valuable contributions to the enhanced understanding of these drugs, and a step closer to personalised medicine in the treatment of cancer.

Subjects/Keywords: actinomycin D; dabrafenib; trametinib; pharmacokinetics; pharmacogenetics; pharmacodynamics

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Kim, H. Y. (2018). Personalised Medicine in the Treatment of Cancer . (Thesis). University of Sydney. Retrieved from http://hdl.handle.net/2123/20103

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Kim, Hannah Yejin. “Personalised Medicine in the Treatment of Cancer .” 2018. Thesis, University of Sydney. Accessed February 27, 2021. http://hdl.handle.net/2123/20103.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Kim, Hannah Yejin. “Personalised Medicine in the Treatment of Cancer .” 2018. Web. 27 Feb 2021.

Vancouver:

Kim HY. Personalised Medicine in the Treatment of Cancer . [Internet] [Thesis]. University of Sydney; 2018. [cited 2021 Feb 27]. Available from: http://hdl.handle.net/2123/20103.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Kim HY. Personalised Medicine in the Treatment of Cancer . [Thesis]. University of Sydney; 2018. Available from: http://hdl.handle.net/2123/20103

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Colorado State University

16. Veselinovic, Milena. Pharmacokinetic and pharmacodynamic evaluation of HIV-1 pre-exposure prophylaxis candidates in humanized mice.

Degree: PhD, Cell and Molecular Biology, 2014, Colorado State University

URL: http://hdl.handle.net/10217/88544

► In the absence of a vaccine, alternative preventative approaches against HIV-1 are needed. In pre-exposure prophylaxis (PrEP) approach, antiretroviral drugs, broadly neutralizing antibodies (bnAb) or… (more)

▼ In the absence of a vaccine, alternative preventative approaches against HIV-1 are needed. In pre-exposure prophylaxis (PrEP) approach, antiretroviral drugs, broadly neutralizing antibodies (bnAb) or other biological molecules are administered orally or topically for the prevention of HIV-1 infection. For successful PrEP design pharmacokinetic (PK) and pharmacodynamic (PD) studies are needed to define protective levels of antiretrovirals in mucosal tissues. The RAG-hu mice used here represent a small animal model in which human immune system is reconstituted by haematopoietic stem cells (HSC) in the immunodefficient BALB/c- Rag1-/- γc-/- and BALB/c- Rag2-/- γc-/- mice. This model was previously shown to be suitable for HIV-1 mucosal transmission and protection studies. In the experiments presented here we evaluated the utility of RAG-hu mice for the study of PK-PD aspects of antiretroviral drugs in the context of PrEP. The PK studies focused on tissue distribution of the RT inhibitor Tenofovir (TFV), the integrase inhibitor Raltegravir (RAL) and the entry inhibitor Maraviroc (MVC) following single and combinatorial oral application. Drug kinetics were examined systemically in blood plasma, and in vaginal, rectal and colonic mucosal tissues, which are the sites of HIV-1 transmission and initial viral spread. Antiretrovirals were applied in human equivalent doses to achieve steady state kinetics. Data obtained from single oral applications verified favorable PrEP profile of TFV. While results showed that RAL and MVC represent promising PrEP candidates, the data suggest that the PrEP doses would need to be higher than therapeutic ones in order to allow for once a day dosing. In combinatorial TFV/RAL and TFV/MVC oral application studies, increase in the active form of TFV (Tenofovir diphosphate, TFV-DP) accompanied by agonistic effect for the second drug in combination was observed, which can be characterized as highly favorable for PrEP applications. This is the first report on combinatorial PK of TFV, RAL and MVC in mucosal tissues which informs further testing of TFV/MVC and TFV/RAL PrEP approaches in non-human primates (NHP) and in clinical settings. For topical PrEP potential, PK profiles of TFV, RAL and MVC were also evaluated in vaginal mucosa following topical application of gel formulations. With all three drugs, one to two log higher concentrations were achieved in vaginal mucosa compared to oral application reflecting previous findings in humans. Intracellular concentrations of TFV-DP in humanized mice corresponded to the levels observed previously in human vaginal mucosa. In PD studies, the protective effect of topical PrEP with single drug and combinatorial TFV, RAL and the RT inhibitor UC781 gels was evaluated against mucosal HIV-1 transmission. High level of protection was seen with combinatorial microbicide gels - 80% (4/5) protection by TFV/UC781 gel and 87.5% (7/8) protection by TFV/RAL gel, indicating their suitability for further testing in preclinical trials. In another PD study, protective… Advisors/Committee Members: Akkina, Ramesh (advisor), Aboellail, Tawfik (committee member), Gonzalez-Juarrero, Mercedes (committee member), Peersen, Olve (committee member).

Subjects/Keywords: HIV-1 mucosal transmission; HIV-1 pre-exposure prophylaxis; humanized mouse model; Maraviroc pharmacokinetics and pharmacodynamics; Raltegravir pharmacokinetcs and pharmacodynamics; Tenofovir pharmacokinetcs and pharmacodynamics

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APA (6^th Edition):

Veselinovic, M. (2014). Pharmacokinetic and pharmacodynamic evaluation of HIV-1 pre-exposure prophylaxis candidates in humanized mice. (Doctoral Dissertation). Colorado State University. Retrieved from http://hdl.handle.net/10217/88544

Chicago Manual of Style (16^th Edition):

Veselinovic, Milena. “Pharmacokinetic and pharmacodynamic evaluation of HIV-1 pre-exposure prophylaxis candidates in humanized mice.” 2014. Doctoral Dissertation, Colorado State University. Accessed February 27, 2021. http://hdl.handle.net/10217/88544.

MLA Handbook (7^th Edition):

Veselinovic, Milena. “Pharmacokinetic and pharmacodynamic evaluation of HIV-1 pre-exposure prophylaxis candidates in humanized mice.” 2014. Web. 27 Feb 2021.

Vancouver:

Veselinovic M. Pharmacokinetic and pharmacodynamic evaluation of HIV-1 pre-exposure prophylaxis candidates in humanized mice. [Internet] [Doctoral dissertation]. Colorado State University; 2014. [cited 2021 Feb 27]. Available from: http://hdl.handle.net/10217/88544.

Council of Science Editors:

Veselinovic M. Pharmacokinetic and pharmacodynamic evaluation of HIV-1 pre-exposure prophylaxis candidates in humanized mice. [Doctoral Dissertation]. Colorado State University; 2014. Available from: http://hdl.handle.net/10217/88544

University of Gothenburg / Göteborgs Universitet

17. Hansson, Roland, 1948-. Postischemic renal damage : protective effects of free radical scavengers and allopurinol in rabbits.

Degree: 1983, University of Gothenburg / Göteborgs Universitet

URL: http://hdl.handle.net/2077/11476

Subjects/Keywords: Medicin Allmänt Allopurinol: pharmacodynamics; Free radicals: pharmacodynamics

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APA (6^th Edition):

Hansson, Roland, 1. (1983). Postischemic renal damage : protective effects of free radical scavengers and allopurinol in rabbits. (Thesis). University of Gothenburg / Göteborgs Universitet. Retrieved from http://hdl.handle.net/2077/11476

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Hansson, Roland, 1948-. “Postischemic renal damage : protective effects of free radical scavengers and allopurinol in rabbits.” 1983. Thesis, University of Gothenburg / Göteborgs Universitet. Accessed February 27, 2021. http://hdl.handle.net/2077/11476.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Hansson, Roland, 1948-. “Postischemic renal damage : protective effects of free radical scavengers and allopurinol in rabbits.” 1983. Web. 27 Feb 2021.

Vancouver:

Hansson, Roland 1. Postischemic renal damage : protective effects of free radical scavengers and allopurinol in rabbits. [Internet] [Thesis]. University of Gothenburg / Göteborgs Universitet; 1983. [cited 2021 Feb 27]. Available from: http://hdl.handle.net/2077/11476.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Hansson, Roland 1. Postischemic renal damage : protective effects of free radical scavengers and allopurinol in rabbits. [Thesis]. University of Gothenburg / Göteborgs Universitet; 1983. Available from: http://hdl.handle.net/2077/11476

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Gothenburg / Göteborgs Universitet

18. Persson, Bengt, 1950-. GABAergic mechanisms in blood pressure control : a pharmacological analysis in the rat.

Degree: 1980, University of Gothenburg / Göteborgs Universitet

URL: http://hdl.handle.net/2077/13584

Subjects/Keywords: Medicin Allmänt Blood pressure: pharmacodynamics; GABA: pharmacodynamics

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APA (6^th Edition):

Persson, Bengt, 1. (1980). GABAergic mechanisms in blood pressure control : a pharmacological analysis in the rat. (Thesis). University of Gothenburg / Göteborgs Universitet. Retrieved from http://hdl.handle.net/2077/13584

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Persson, Bengt, 1950-. “GABAergic mechanisms in blood pressure control : a pharmacological analysis in the rat.” 1980. Thesis, University of Gothenburg / Göteborgs Universitet. Accessed February 27, 2021. http://hdl.handle.net/2077/13584.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Persson, Bengt, 1950-. “GABAergic mechanisms in blood pressure control : a pharmacological analysis in the rat.” 1980. Web. 27 Feb 2021.

Vancouver:

Persson, Bengt 1. GABAergic mechanisms in blood pressure control : a pharmacological analysis in the rat. [Internet] [Thesis]. University of Gothenburg / Göteborgs Universitet; 1980. [cited 2021 Feb 27]. Available from: http://hdl.handle.net/2077/13584.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Persson, Bengt 1. GABAergic mechanisms in blood pressure control : a pharmacological analysis in the rat. [Thesis]. University of Gothenburg / Göteborgs Universitet; 1980. Available from: http://hdl.handle.net/2077/13584

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Gothenburg / Göteborgs Universitet

19. Volkmann, Reinhard, 1942-. Inverkan av katekolaminer och Ca++-antagonister på hjärtats elektromekaniska aktivitet = [Effects of catecholamines and calcium blockers on cardiac electrical and mechanical activities].

Degree: 1985, University of Gothenburg / Göteborgs Universitet

URL: http://hdl.handle.net/2077/15008

Subjects/Keywords: Medicin Allmänt Calcium channel blockers: pharmacodynamics; Catecholamines: pharmacodynamics

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APA (6^th Edition):

Volkmann, Reinhard, 1. (1985). Inverkan av katekolaminer och Ca++-antagonister på hjärtats elektromekaniska aktivitet = [Effects of catecholamines and calcium blockers on cardiac electrical and mechanical activities]. (Thesis). University of Gothenburg / Göteborgs Universitet. Retrieved from http://hdl.handle.net/2077/15008

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Volkmann, Reinhard, 1942-. “Inverkan av katekolaminer och Ca++-antagonister på hjärtats elektromekaniska aktivitet = [Effects of catecholamines and calcium blockers on cardiac electrical and mechanical activities].” 1985. Thesis, University of Gothenburg / Göteborgs Universitet. Accessed February 27, 2021. http://hdl.handle.net/2077/15008.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Volkmann, Reinhard, 1942-. “Inverkan av katekolaminer och Ca++-antagonister på hjärtats elektromekaniska aktivitet = [Effects of catecholamines and calcium blockers on cardiac electrical and mechanical activities].” 1985. Web. 27 Feb 2021.

Vancouver:

Volkmann, Reinhard 1. Inverkan av katekolaminer och Ca++-antagonister på hjärtats elektromekaniska aktivitet = [Effects of catecholamines and calcium blockers on cardiac electrical and mechanical activities]. [Internet] [Thesis]. University of Gothenburg / Göteborgs Universitet; 1985. [cited 2021 Feb 27]. Available from: http://hdl.handle.net/2077/15008.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Volkmann, Reinhard 1. Inverkan av katekolaminer och Ca++-antagonister på hjärtats elektromekaniska aktivitet = [Effects of catecholamines and calcium blockers on cardiac electrical and mechanical activities]. [Thesis]. University of Gothenburg / Göteborgs Universitet; 1985. Available from: http://hdl.handle.net/2077/15008

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

20. Keizer, R.J. Pharmacometrics in early clinical drug development.

Degree: 2010, University Utrecht

URL: https://dspace.library.uu.nl/handle/1874/179786 ; URN:NBN:NL:UI:10-1874-179786 ; 1874/179786 ; urn:isbn:9789090256320 ; URN:NBN:NL:UI:10-1874-179786 ; https://dspace.library.uu.nl/handle/1874/179786

► Pharmacometrics, the science of quantitative clinical pharmacology, has been recognized as one of the main research fields able to improve efficiency in drug development, and… (more)

▼ Pharmacometrics, the science of quantitative clinical pharmacology, has been recognized as one of the main research fields able to improve efficiency in drug development, and to reduce attrition rates on the route from drug discovery to approval. This field of drug research, which builds heavily on the sciences of mathematics, statistics, pharmacology and biology, provides a tool for studying relationships between drug exposure and drug effects. This thesis concerns the application of pharmacometrics in the early clinical development of drugs, and has a strong focus on oncology. The thesis shows that the use of population modelling & simulation greatly facilitates the appropriate handling of all available data, including data which may be difficult to handle using standard approaches (e.g. missing, censored or baseline data). It is shown here that, especially when faced with such limitations or challenges, the use of modeling techniques instead of reliance on the more conventional statistical techniques, allows the most appropriate and data-efficient analysis of data. Of course, this is especially relevant when data is sparse or associated with high variability, which is often the case in (early) clinical studies. The thesis shows that the use of pharmacodynamic biomarkers in a PK-PD analysis can greatly support the early clinical development of new drugs. Several pharmacokinetic-pharmacodynamic (PK-PD) analyses in early drug development are presented in the thesis, incorporating a PD biomarker for efficacy or toxicity. One of the chapters presents the construction of a model for the occurrence of hypertension and proteinuria toxicity during treatment with a novel anticancer drug, based on early clinical data. Subsequent simulations using this model provided support for the hypertension intervention scheme proposed for Phase II clinical development, and showed that intra-patient dose escalations using hypertension as a biomarker may be feasible without inducing considerable toxicity. In another analysis, preclinical and early clinical biomarker and tumour growth data were combined to allow an early assessment of anticancer activity of another novel drug. In two other chapters, investigations into the predictive ability and schedule-dependency of a PK-PD model for haematological toxicity during treatment with anticancer drugs are described. When modelling early clinical or preclinical data, the modeller is often confronted with technical difficulties concerning incomplete data. In the final section of the thesis, investigations are presented into two such problems: data below the limit of quantification (BLOQ) and incomplete covariate datasets. For the former problem, it was shown that the use of extrapolated BLOQ concentration data provides superior performance over established methods. For the latter problem, an approach in which an extra parameter for covariate effect was estimated for the group in which data on the covariate was missing, provided the easiest and most robust performance to analyses such datasets.… Advisors/Committee Members: Schellens, J.H.M., Beijnen, J.H., Huitema, A.D.R..

Subjects/Keywords: pharmacometrics; pharmacokinetics; pharmacodynamics; pharmacodynamics; drug development; oncology; cancer

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Keizer, R. J. (2010). Pharmacometrics in early clinical drug development. (Doctoral Dissertation). University Utrecht. Retrieved from https://dspace.library.uu.nl/handle/1874/179786 ; URN:NBN:NL:UI:10-1874-179786 ; 1874/179786 ; urn:isbn:9789090256320 ; URN:NBN:NL:UI:10-1874-179786 ; https://dspace.library.uu.nl/handle/1874/179786

Chicago Manual of Style (16^th Edition):

Keizer, R J. “Pharmacometrics in early clinical drug development.” 2010. Doctoral Dissertation, University Utrecht. Accessed February 27, 2021. https://dspace.library.uu.nl/handle/1874/179786 ; URN:NBN:NL:UI:10-1874-179786 ; 1874/179786 ; urn:isbn:9789090256320 ; URN:NBN:NL:UI:10-1874-179786 ; https://dspace.library.uu.nl/handle/1874/179786.

MLA Handbook (7^th Edition):

Keizer, R J. “Pharmacometrics in early clinical drug development.” 2010. Web. 27 Feb 2021.

Vancouver:

Keizer RJ. Pharmacometrics in early clinical drug development. [Internet] [Doctoral dissertation]. University Utrecht; 2010. [cited 2021 Feb 27]. Available from: https://dspace.library.uu.nl/handle/1874/179786 ; URN:NBN:NL:UI:10-1874-179786 ; 1874/179786 ; urn:isbn:9789090256320 ; URN:NBN:NL:UI:10-1874-179786 ; https://dspace.library.uu.nl/handle/1874/179786.

Council of Science Editors:

Keizer RJ. Pharmacometrics in early clinical drug development. [Doctoral Dissertation]. University Utrecht; 2010. Available from: https://dspace.library.uu.nl/handle/1874/179786 ; URN:NBN:NL:UI:10-1874-179786 ; 1874/179786 ; urn:isbn:9789090256320 ; URN:NBN:NL:UI:10-1874-179786 ; https://dspace.library.uu.nl/handle/1874/179786

Universiteit Utrecht

21. Zandvliet, A.S. Population pharmacokinetic and pharmacodynamic modeling and simulation of the investigational anticancer agent indisulam.

Degree: 2007, Universiteit Utrecht

URL: http://dspace.library.uu.nl:8080/handle/1874/22763

► Indisulam is an investigational anticancer agent that is currently being evaluated in phase II clinical studies. The aim of this thesis was to develop a… (more)

▼ Indisulam is an investigational anticancer agent that is currently being evaluated in phase II clinical studies. The aim of this thesis was to develop a mechanism-based pharmacokinetic and pharmacodynamic model for indisulam-induced myelosuppression and to apply this model as a tool for treatment optimization. This may assist further clinical development of this drug. Indisulam has a highly non-linear concentration-time profile, indicating complex underlying pharmacokinetic processes. The profound non-linearity and the wide variability between patients contributed to poorly predictable drug exposure after treatment with indisulam. A semi-physiological population pharmacokinetic model of indisulam was developed to gain further knowledge and understanding of the disposition of indisulam. Neutropenia and thrombocytopenia were identified as the dose limiting toxicities of indisulam. A subset of patients developed grade 4 neutropenia, the most severe grade according to the Common Toxicity Criteria (CTC) and were at risk of developing serious and rapidly progressing infections. A semi-physiological population pharmacokinetic and pharmacodynamic model was used to describe the time profile of neutropenia and thrombocytopenia after administration of indisulam. Treatment with indisulam was complicated, mainly because the severity of indisulam-induced haematological toxicity was poorly predictable. An extensive covariate analysis was performed to identify pharmacokinetic and pharmacodynamic determinants of indisulam. Low body surface area, Japanese race, variant CYP2C genotype, low baseline neutrophil and thrombocyte counts and female sex were identified as clinically relevant risk factors. An algorithm for dose individualization was developed, which may assist in safe dosing of indisulam. Indisulam is currently evaluated in combination regimens. Indisulam in combination with capecitabine was well tolerated in the first treatment cycle, but severe myelotoxicity was observed after the second treatment cycle. A time-dependent drug-drug interaction was identified by population PK-PD modeling. The combination of 550 mg/m2 indisulam and 1250 mg/m2 capecitabine BID was predicted to be safe and feasible for future studies. The combination of indisulam and carboplatin was not tolerable in a 3-weekly regimen, because a delay of re-treatment was frequently required to allow recovery from myelosuppression from previous cycles. A PK-PD model was developed and used to evaluate 3-weekly and 4-weekly administration regimens of various doses of the combination indisulam-carboplatin. This study supported the selection of 500 mg/m2 indisulam in combination with 6 mg.min/ml carboplatin in a 4-weekly regimen as the recommended dose for future studies. A safe dose of indisulam in various administration schedules was previously defined in four parallel phase I dose escalation studies. We proposed a new clinical trial design to increase the efficiency of a phase I program. The method proved to be equally safe as the conventional design, the number of…

Subjects/Keywords: Farmacie; pharmacokinetics; pharmacodynamics; indisulam; modeling; simulation; clinical; oncology; pharmacology; myelosuppression; neutropenia

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APA (6^th Edition):

Zandvliet, A. S. (2007). Population pharmacokinetic and pharmacodynamic modeling and simulation of the investigational anticancer agent indisulam. (Doctoral Dissertation). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/22763

Chicago Manual of Style (16^th Edition):

Zandvliet, A S. “Population pharmacokinetic and pharmacodynamic modeling and simulation of the investigational anticancer agent indisulam.” 2007. Doctoral Dissertation, Universiteit Utrecht. Accessed February 27, 2021. http://dspace.library.uu.nl:8080/handle/1874/22763.

MLA Handbook (7^th Edition):

Zandvliet, A S. “Population pharmacokinetic and pharmacodynamic modeling and simulation of the investigational anticancer agent indisulam.” 2007. Web. 27 Feb 2021.

Vancouver:

Zandvliet AS. Population pharmacokinetic and pharmacodynamic modeling and simulation of the investigational anticancer agent indisulam. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2007. [cited 2021 Feb 27]. Available from: http://dspace.library.uu.nl:8080/handle/1874/22763.

Council of Science Editors:

Zandvliet AS. Population pharmacokinetic and pharmacodynamic modeling and simulation of the investigational anticancer agent indisulam. [Doctoral Dissertation]. Universiteit Utrecht; 2007. Available from: http://dspace.library.uu.nl:8080/handle/1874/22763

Universiteit Utrecht

22. Klümpen, H.J. Personalized medicine of targeted anti-cancer drugs.

Degree: 2012, Universiteit Utrecht

URL: http://dspace.library.uu.nl:8080/handle/1874/234354

► Medicine is becoming more and more tailored and that certainly applies to therapies for cancer. The researcher has looked at the genetic profile of the… (more)

Subjects/Keywords: Farmacie; pharmacogenetics; pharmacodynamics; targeted therapies; mTOR inhibitors; imatinib; sunitinib

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Klümpen, H. J. (2012). Personalized medicine of targeted anti-cancer drugs. (Doctoral Dissertation). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/234354

Chicago Manual of Style (16^th Edition):

Klümpen, H J. “Personalized medicine of targeted anti-cancer drugs.” 2012. Doctoral Dissertation, Universiteit Utrecht. Accessed February 27, 2021. http://dspace.library.uu.nl:8080/handle/1874/234354.

MLA Handbook (7^th Edition):

Klümpen, H J. “Personalized medicine of targeted anti-cancer drugs.” 2012. Web. 27 Feb 2021.

Vancouver:

Klümpen HJ. Personalized medicine of targeted anti-cancer drugs. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2012. [cited 2021 Feb 27]. Available from: http://dspace.library.uu.nl:8080/handle/1874/234354.

Council of Science Editors:

Klümpen HJ. Personalized medicine of targeted anti-cancer drugs. [Doctoral Dissertation]. Universiteit Utrecht; 2012. Available from: http://dspace.library.uu.nl:8080/handle/1874/234354

Universiteit Utrecht

23. Leijen, S. Development of Combination Therapy with Anti-Cancer Drugs.

Degree: 2013, Universiteit Utrecht

URL: http://dspace.library.uu.nl:8080/handle/1874/267996

► This thesis describes early clinical trials with anti-cancer drugs in combination with commonly applied and registered chemotherapy and single agent studies with compounds that are… (more)

▼ This thesis describes early clinical trials with anti-cancer drugs in combination with commonly applied and registered chemotherapy and single agent studies with compounds that are intended for use in combination with registered or other targeted anti-cancer drugs. Gemcitabine is a prodrug that first needs to be metabolized in the body in order to exert its action. Fixed dose-rate infusion, an infusion at a lower speed, is a concept that takes into account the rate-limiting step of the activating enzyme deoxycytidine kinase (dCK). This new application of an existing drug was investigated in combination with carboplatin in ovarian cancer patients after first-line therapy and demonstrated that fixed dose-rate gemcitabine in combination with carboplatin in the applied schedule results in increased grade 3/4 toxicity compared to conventional 30-minute infused gemcitabine. Ruthenium is a heavy metal like platinum and ruthenium derivatives have been developed with the objective to create drugs as powerful as cisplatin, but with limited adverse events. NAMI-A was the first ruthenium derivative that has been evaluated in a clinical setting, as a single agent. Promising preclinical results of the combination of NAMI-A and gemcitabine resulted in a clinical study with these two agents in non-small cell lung cancer (NSCLC) patients after first-line therapy. NAMI-A was moderately tolerated and expansion of the phase II part was not conducted because the predefined number of responses was not reached. MEK inhibitors are an example of targeted anti-cancer drugs. MEK is part of the MAPK pathway. MAPKs are initiated by ligand binding at the cell surface and ultimately lead to gene transcription in the nucleus. Genetic alterations can lead to overexpression and aberrant activation downstream of the mutation. Selumetinib, a relatively older, second generation MEK inhibitor, was first developed as a mix and drink formulation. A food-effect study with a new capsule formulation with improved pharmacological properties demonstrated that the presence of food decreased the extent and rate of absorption of selumetinib. A phase I study with the newer MEK inhibitor RO4987655 conducted in patients with different kinds of solid tumors defined the maximal tolerable dose (MTD) at 8.5 mg BID and demonstrated an acceptable toxicity profile. MK-1775 is a selective inhibitor of protein Wee1, a key player in the G2 checkpoint and is thought to be especially active in cancer cells with p53 pathway mutations. Many tumors harbor p53 mutations, which make cancer cells more dependent on the G2 checkpoint for DNA repair. By inducing DNA damage with chemotherapy and pharmacological inhibition of Wee1 by MK-1775 apoptosis can be induced especially in tumor cells. A preliminary analysis of the first in human phase I study with MK-1775 in combination with gemcitabine, cisplatin or carboplatin showed that MK-1775 was well tolerated and has a developable pharmacokinetic profile. Preliminary results of the ongoing proof of concept phase II study… Advisors/Committee Members: Schellens, J.H.M., Beijnen, J.H..

Subjects/Keywords: Farmacie; Drug development; Cancer; Clinical trial; Pharmacokinetics; Pharmacodynamics; Chemotherapy

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Leijen, S. (2013). Development of Combination Therapy with Anti-Cancer Drugs. (Doctoral Dissertation). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/267996

Chicago Manual of Style (16^th Edition):

Leijen, S. “Development of Combination Therapy with Anti-Cancer Drugs.” 2013. Doctoral Dissertation, Universiteit Utrecht. Accessed February 27, 2021. http://dspace.library.uu.nl:8080/handle/1874/267996.

MLA Handbook (7^th Edition):

Leijen, S. “Development of Combination Therapy with Anti-Cancer Drugs.” 2013. Web. 27 Feb 2021.

Vancouver:

Leijen S. Development of Combination Therapy with Anti-Cancer Drugs. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2013. [cited 2021 Feb 27]. Available from: http://dspace.library.uu.nl:8080/handle/1874/267996.

Council of Science Editors:

Leijen S. Development of Combination Therapy with Anti-Cancer Drugs. [Doctoral Dissertation]. Universiteit Utrecht; 2013. Available from: http://dspace.library.uu.nl:8080/handle/1874/267996

Universiteit Utrecht

24. van Hasselt, J.G.C. Integrated quantitative pharmacology for treatment optimization in oncology.

Degree: 2014, Universiteit Utrecht

URL: http://dspace.library.uu.nl:8080/handle/1874/309225

► This thesis describes the development and application of quantitative pharmacological models in oncology for treatment optimization and for the design and analysis of clinical trials… (more)

▼ This thesis describes the development and application of quantitative pharmacological models in oncology for treatment optimization and for the design and analysis of clinical trials with respect to pharmacokinetics, toxicity, efficacy and cost-effectiveness. A recurring theme throughout this thesis is the quantitative integration of available knowledge during the development of a model. The utility of such integrative approaches relates to the fact that usually some relevant pre-existing knowledge exists, for instance related to physiology, pharmacokinetics or pharmacodynamics. Across different chapters in this thesis we have studied how such knowledge can be integrated in models to increase their predictive value or clinical utility. A second motivation for integrative approaches is the multi-factorial character of treatment of individual patients, or the design of clinical trials. The first part of this thesis demonstrated the development of model-based approaches for the design and analysis of studies in special patient populations including children, pregnant patients and patients with renal impairment. A clinical trial simulation was conducted for a drug-drug interaction study in pediatric oncology patients. Subsequently we describe the development of a model quantifying changes in pharmacokinetics for four frequently used anticancer agents in pregnant cancer patients. Finally we showed how integration of established physiological changes during pregnancy can be used to support the prediction and analysis of pharmacokinetic studies in pregnant patients. In the next part we developed quantitative dynamical models for toxicities. A semi-physiological model for eribulin-induced neutropenia was developed and applied to derive improved dosing strategies. A second toxicity model described trastuzumab-induced cardiotoxicity, which was then used to improve cardiac monitoring protocols. In the last part of this thesis we first describe the development of a disease-progression model for castration-resistant prostate cancer in patients treated with eribulin, and the subsequent integration of models for toxicity, efficacy and cost-effectiveness that can be potentially used to support decision-making during early drug development. The last chapters describe the development of a generic simulation framework for cost-effectiveness models and an evaluation of the impact of structural uncertainty in such models. Advisors/Committee Members: Schellens, Johannes, Beijnen, Jacob, Huitema, A.D.R..

Subjects/Keywords: pharmacokinetics; pharmacodynamics; oncology; clinical pharmacology; modelling; pharmacometrics; special populations; drug development

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

van Hasselt, J. G. C. (2014). Integrated quantitative pharmacology for treatment optimization in oncology. (Doctoral Dissertation). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/309225

Chicago Manual of Style (16^th Edition):

van Hasselt, J G C. “Integrated quantitative pharmacology for treatment optimization in oncology.” 2014. Doctoral Dissertation, Universiteit Utrecht. Accessed February 27, 2021. http://dspace.library.uu.nl:8080/handle/1874/309225.

MLA Handbook (7^th Edition):

van Hasselt, J G C. “Integrated quantitative pharmacology for treatment optimization in oncology.” 2014. Web. 27 Feb 2021.

Vancouver:

van Hasselt JGC. Integrated quantitative pharmacology for treatment optimization in oncology. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2014. [cited 2021 Feb 27]. Available from: http://dspace.library.uu.nl:8080/handle/1874/309225.

Council of Science Editors:

van Hasselt JGC. Integrated quantitative pharmacology for treatment optimization in oncology. [Doctoral Dissertation]. Universiteit Utrecht; 2014. Available from: http://dspace.library.uu.nl:8080/handle/1874/309225

University of Utah

25. LaPierre, Cristen Doyle. Identification of optimal dosing regimens for procedures requiring esophageal instrumentation through multiobjective optimization.

Degree: PhD, Bioengineering, 2010, University of Utah

URL: http://content.lib.utah.edu/cdm/singleitem/collection/etd3/id/294/rec/1283

► The use of propofol and propofol in combination with remifentanil by nonanesthesiologists is a controversial topic. Much of the concern centers on adverse respiratory effects:… (more)

▼ The use of propofol and propofol in combination with remifentanil by nonanesthesiologists is a controversial topic. Much of the concern centers on adverse respiratory effects: loss of responsiveness, respiratory depression, and airway obstruction. The aim of this study was to investigate these adverse drug effects at propofol-remifentanil combinations commonly used in procedures requiring esophageal instrumentation and build response surface models of drug effects. A second aim was to investigate published dosing regimens through simulation with these models. A third aim was to develop an optimization algorithm to identify an ideal propofol-remifentanil dosing regimen for upper endoscopy procedures. Twenty-four volunteers received escalating target controlled remifentanil and propofol infusions. Responses to insertion of a bougie (40 cm), responsiveness, respiratory rate, and tidal volume were recorded at 384 targeted concentration pairs. Four published dosing regimens of propofol alone or in combination with opioids were simulated for a 10-min procedure. An optimization algorithm was developed to identify an optimal propofol-remifentanil dosing regimen from a set of possibilities. Models for loss of response to esophageal instrumentation, intolerable ventilatory depression, and respiratory compromise were built. Simulations of published dosing regimens showed that once drug administration ended, loss of responsiveness, and respiratory depression effects dissipated quickly. Respiratory compromise dissipated more quickly in propofol only techniques compared to propofol-opioid techniques. An optimal dosing recommendation was identified for a simulated 55 year-old, 75 kg, 175 cm male undergoing an anticipated 10-min upper endoscopy and consisted of a propofol bolus of 0.8 mg/kg and infusion rate of 40 mcg/kg/min and a remifentanil bolus of 0.2 mcg/kg and an infusion rate of 0.05 mcg/kg/min. High propofol-low remifentanil concentration pairs can block the response to esophageal instrumentation while avoiding intolerable ventilatory depression in spontaneously breathing volunteers. Propofol combined with remifentanil or fentanyl improved conditions for esophageal instrumentation and had a rapid return to responsiveness. Optimization techniques identified a remifentanil propofol dosing regimen that minimizes the duration of loss of responsiveness, respiratory depression, and airway obstruction and, according to expert opinion and models of drug effect, provides conditions that will permit upper endoscopy procedures. This dosing regimen merits clinical validation in patients undergoing brief endoscopic procedures.

Subjects/Keywords: Endoscopy; Multiobjective optimization; Optimal dosing; Pharmacodynamics; Propofol; Remifentanil

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APA (6^th Edition):

LaPierre, C. D. (2010). Identification of optimal dosing regimens for procedures requiring esophageal instrumentation through multiobjective optimization. (Doctoral Dissertation). University of Utah. Retrieved from http://content.lib.utah.edu/cdm/singleitem/collection/etd3/id/294/rec/1283

Chicago Manual of Style (16^th Edition):

LaPierre, Cristen Doyle. “Identification of optimal dosing regimens for procedures requiring esophageal instrumentation through multiobjective optimization.” 2010. Doctoral Dissertation, University of Utah. Accessed February 27, 2021. http://content.lib.utah.edu/cdm/singleitem/collection/etd3/id/294/rec/1283.

MLA Handbook (7^th Edition):

LaPierre, Cristen Doyle. “Identification of optimal dosing regimens for procedures requiring esophageal instrumentation through multiobjective optimization.” 2010. Web. 27 Feb 2021.

Vancouver:

LaPierre CD. Identification of optimal dosing regimens for procedures requiring esophageal instrumentation through multiobjective optimization. [Internet] [Doctoral dissertation]. University of Utah; 2010. [cited 2021 Feb 27]. Available from: http://content.lib.utah.edu/cdm/singleitem/collection/etd3/id/294/rec/1283.

Council of Science Editors:

LaPierre CD. Identification of optimal dosing regimens for procedures requiring esophageal instrumentation through multiobjective optimization. [Doctoral Dissertation]. University of Utah; 2010. Available from: http://content.lib.utah.edu/cdm/singleitem/collection/etd3/id/294/rec/1283

Rochester Institute of Technology

26. O'Shaughnessy, Brian. The Synthesis and Characteristics of Nonsteroidal Antiestrogens; Hydroxytamoxifen and N,N-Dimethyl Analog of Nafoxidine.

Degree: School of Chemistry and Materials Science (COS), 1984, Rochester Institute of Technology

URL: https://scholarworks.rit.edu/theses/3719

► Introductory Remarks and Statement of Purpose: Estrogens and estrogen mimetic compounds have long been known to be potent growth promoters. It is also well… (more)

▼ Introductory Remarks and Statement of Purpose: Estrogens and estrogen mimetic compounds have long been known to be potent growth promoters. It is also well established that within the cells of estrogen target organs there are proteins which act as specific receptors and as such bind estrogen against a concentration gradient (1). Additionally, these proteins are capable of carrying the estrogenic molecule across the nuclear membrane in an as yet not fully understood, thermally activated mechanism. Once inside the nucleus, the estrogenic molecule (that is estrogenic in binding ability) will then either enhance or diminish transcription, translocation, and subsequently protein growth. As growth promoters, the estrogens have also been found to enhance the growth of some forms of tumor tissue, which mimic classic estrogen target organs. As such the need for effective anti-estrogens becomes clear in that minimizing the amount of estrogen available (or the degree to which it can be utilized) it is possible to reduce or even negate the growth of hormone-responsive tumors. The exact nature of what constitutes an estrogenic versus anti-estrogenic compound remains mechanistically uncertain and subsequently has relied largely on empirical data and related rationalizations. The comparison series found in Figure 1 illustrates some of the fundamental characteristics considered to be of importance regarding the efficacy of any particular antagonist in relation to several agonists. For example, the nonpolar aromatic side chain, as well as the aminoether side chain are thought to be of key importance in the effective antagonism of the estrogenic response. Furthermore, there is an activated estrogen-receptor complex known to be crucial to the induction of protein synthesis which seems a likely avenue through which effective estrogen antagonism may be pursued. This plan of attack is more viable in view of the so called promiscuous nature of the estrogen receptor, which is to say that it is susceptible to binding with compounds other than its' intended. Subsequently, strong, irreversible binding of the receptor to a biologically inactive compound is considered of key importance to effective estrogen antagonism. Advisors/Committee Members: Henzel, Kay.

Subjects/Keywords: Estrogen; Growth promoters; Pharmacodynamics; Thesis

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

O'Shaughnessy, B. (1984). The Synthesis and Characteristics of Nonsteroidal Antiestrogens; Hydroxytamoxifen and N,N-Dimethyl Analog of Nafoxidine. (Thesis). Rochester Institute of Technology. Retrieved from https://scholarworks.rit.edu/theses/3719

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

O'Shaughnessy, Brian. “The Synthesis and Characteristics of Nonsteroidal Antiestrogens; Hydroxytamoxifen and N,N-Dimethyl Analog of Nafoxidine.” 1984. Thesis, Rochester Institute of Technology. Accessed February 27, 2021. https://scholarworks.rit.edu/theses/3719.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

O'Shaughnessy, Brian. “The Synthesis and Characteristics of Nonsteroidal Antiestrogens; Hydroxytamoxifen and N,N-Dimethyl Analog of Nafoxidine.” 1984. Web. 27 Feb 2021.

Vancouver:

O'Shaughnessy B. The Synthesis and Characteristics of Nonsteroidal Antiestrogens; Hydroxytamoxifen and N,N-Dimethyl Analog of Nafoxidine. [Internet] [Thesis]. Rochester Institute of Technology; 1984. [cited 2021 Feb 27]. Available from: https://scholarworks.rit.edu/theses/3719.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

O'Shaughnessy B. The Synthesis and Characteristics of Nonsteroidal Antiestrogens; Hydroxytamoxifen and N,N-Dimethyl Analog of Nafoxidine. [Thesis]. Rochester Institute of Technology; 1984. Available from: https://scholarworks.rit.edu/theses/3719

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

27. 大島, 一浩. Efficacy of High-Dose Meropenem (6 g/day) in the Treatment of Experimental Murine Pneumonia Induced by Meropenem-resistant Pseudomonas aeruginosa : メロペネム耐性緑膿菌による肺炎に対する高用量メロペネム(6g/day)の効果の検討.

Degree: 博士(医学), 2016, Nagasaki University / 長崎大学

URL: http://hdl.handle.net/10069/37694

► High-dose meropenem (MEPM; 6 g/day) has been approved as a treatment for purulent meningitis; however, little is known regarding its in vivo efficacy in refractory… (more)

Subjects/Keywords: high dose; meropenem; pharmacokinetics/pharmacodynamics; meropenem-resistant Pseudomonas aeruginosa

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APA (6^th Edition):

大島, �. (2016). Efficacy of High-Dose Meropenem (6 g/day) in the Treatment of Experimental Murine Pneumonia Induced by Meropenem-resistant Pseudomonas aeruginosa : メロペネム耐性緑膿菌による肺炎に対する高用量メロペネム(6g/day)の効果の検討. (Thesis). Nagasaki University / 長崎大学. Retrieved from http://hdl.handle.net/10069/37694

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

大島, 一浩. “Efficacy of High-Dose Meropenem (6 g/day) in the Treatment of Experimental Murine Pneumonia Induced by Meropenem-resistant Pseudomonas aeruginosa : メロペネム耐性緑膿菌による肺炎に対する高用量メロペネム(6g/day)の効果の検討.” 2016. Thesis, Nagasaki University / 長崎大学. Accessed February 27, 2021. http://hdl.handle.net/10069/37694.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

大島, 一浩. “Efficacy of High-Dose Meropenem (6 g/day) in the Treatment of Experimental Murine Pneumonia Induced by Meropenem-resistant Pseudomonas aeruginosa : メロペネム耐性緑膿菌による肺炎に対する高用量メロペネム(6g/day)の効果の検討.” 2016. Web. 27 Feb 2021.

Vancouver:

大島 �. Efficacy of High-Dose Meropenem (6 g/day) in the Treatment of Experimental Murine Pneumonia Induced by Meropenem-resistant Pseudomonas aeruginosa : メロペネム耐性緑膿菌による肺炎に対する高用量メロペネム(6g/day)の効果の検討. [Internet] [Thesis]. Nagasaki University / 長崎大学; 2016. [cited 2021 Feb 27]. Available from: http://hdl.handle.net/10069/37694.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

大島 �. Efficacy of High-Dose Meropenem (6 g/day) in the Treatment of Experimental Murine Pneumonia Induced by Meropenem-resistant Pseudomonas aeruginosa : メロペネム耐性緑膿菌による肺炎に対する高用量メロペネム(6g/day)の効果の検討. [Thesis]. Nagasaki University / 長崎大学; 2016. Available from: http://hdl.handle.net/10069/37694

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

28. Oliveira, Juliana da Silva [UNESP]. Avaliação de Tecnologia em Saúde: fatores associados ao nível sérico de vancomicina e impacto do ajuste de dose sobre o prognóstico de pacientes adultos internados no Hospital das Clínicas da Faculdade de Medicina de Botucatu.

Degree: 2016, Universidade Estadual Paulista

URL: http://hdl.handle.net/11449/143843

►

Objetivos: Questionamentos têm sido lançados sobre a eficácia das formulações genéricas de vancomicina, empregadas com frequência nos países em desenvolvimento. No entanto, a grande disponibilidade… (more)

▼

Objetivos: Questionamentos têm sido lançados sobre a eficácia das formulações genéricas de vancomicina, empregadas com frequência nos países em desenvolvimento. No entanto, a grande disponibilidade de testes para monitorar a concentração de vancomicina no soro tornou possível ajustar as doses, a fim de melhorar os resultados. Nosso estudo teve como objetivo descrever os padrões de prescrição e monitorização de dose sérica de vancomicina genérica em um hospital brasileiro. Estávamos especialmente interessados no impacto desses parâmetros sobre o prognóstico de pacientes. Métodos: Uma coorte retrospectiva de 513 pacientes adultos que foram tratados com vancomicina em 2014 foi estudada. Desfechos de interesse foram: (a) atingir concentrações séricas mínimas sub-ótimas na primeira ocasião de monitoramento e (b) morte dentro de 30 dias da introdução vancomicina. A análise multivariada (regressão logística e de Cox) foi aplicada. Resultados: Menos de 25% dos indivíduos alcançaram concentração sérica mínima ótima (15-20 mg/L), mesmo depois de cinco testes e ajustes posológicos. No entanto, a soma dos indivíduos que apresentaram concentrações ideais e altas foi predominante em cada teste. Doença renal (OR = 4,86, IC95% = 2,05-11,53, P <0,001) e dose diária (OR para mg/kg = 1,04, IC95% = 1,01-1,07, P = 0,01) foram positivamente associada com níveis mais elevados de vancomicina. Além disso, indivíduos mais jovens eram menos propensos a apresentar baixa concentração sérica. Na análise de sobrevivência, as concentrações ideais foram associadas com melhores desfechos, mas apenas aqueles com níveis elevados apresentaram aumento significativo do risco (HR = 1,80, IC95% = 1,05-3,07, P = 0,03). Conclusão: Os resultados alertam para riscos de toxicidade com altas concentrações de vancomicina. O ajuste fino da posologia (por exemplo, com infusão contínua) pode contribuir para melhorar a segurança e eficácia.

Objectives: Concerns have been raised about generic formulations of vancomycin – especially in developing countries – but the wide availability of tests for monitoring serum vancomycin concentration made it possible to adjust doses in order to improve outcomes. We aimed at describing patterns of generic vancomycin prescription and monitoring in a Brazilian hospital and their impact on outcomes. Methods: A cohort of 513 adult patients who were treated with vancomycin in year 2014 was retrospectively studied. Outcomes of interest were achieving suboptimal serum trough concentrations in the first serum monitoring and death within 30 days of vancomycin introduction. Multivariable analysis (logistic and Cox regression was applied) Results: Less than 25% of subjects achieved optimal (15-20 mg/L) trough concentrations, even after five tests and dosing adjustments. However, the sum of subjects presenting optimal and high concentrations was predominant in each and every test. Renal disease (OR=4.86, 95%CI=2.05-11.53, P<0.001) and daily dosing (OR for mg/kg =1.04, IC95%=1.01-1.07, P=0.01) were positively associated with higher…

Advisors/Committee Members: Fortaleza, Carlos Magno Castelo Branco [UNESP], Universidade Estadual Paulista (UNESP).

Subjects/Keywords: Vancomicina; Farmacocinética; Farmacodinâmica; Prognóstico; Vancomycin; Pharmacokinetics; Pharmacodynamics; Outcome

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APA (6^th Edition):

Oliveira, J. d. S. [. (2016). Avaliação de Tecnologia em Saúde: fatores associados ao nível sérico de vancomicina e impacto do ajuste de dose sobre o prognóstico de pacientes adultos internados no Hospital das Clínicas da Faculdade de Medicina de Botucatu. (Thesis). Universidade Estadual Paulista. Retrieved from http://hdl.handle.net/11449/143843

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Oliveira, Juliana da Silva [UNESP]. “Avaliação de Tecnologia em Saúde: fatores associados ao nível sérico de vancomicina e impacto do ajuste de dose sobre o prognóstico de pacientes adultos internados no Hospital das Clínicas da Faculdade de Medicina de Botucatu.” 2016. Thesis, Universidade Estadual Paulista. Accessed February 27, 2021. http://hdl.handle.net/11449/143843.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Oliveira, Juliana da Silva [UNESP]. “Avaliação de Tecnologia em Saúde: fatores associados ao nível sérico de vancomicina e impacto do ajuste de dose sobre o prognóstico de pacientes adultos internados no Hospital das Clínicas da Faculdade de Medicina de Botucatu.” 2016. Web. 27 Feb 2021.

Vancouver:

Oliveira JdS[. Avaliação de Tecnologia em Saúde: fatores associados ao nível sérico de vancomicina e impacto do ajuste de dose sobre o prognóstico de pacientes adultos internados no Hospital das Clínicas da Faculdade de Medicina de Botucatu. [Internet] [Thesis]. Universidade Estadual Paulista; 2016. [cited 2021 Feb 27]. Available from: http://hdl.handle.net/11449/143843.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Oliveira JdS[. Avaliação de Tecnologia em Saúde: fatores associados ao nível sérico de vancomicina e impacto do ajuste de dose sobre o prognóstico de pacientes adultos internados no Hospital das Clínicas da Faculdade de Medicina de Botucatu. [Thesis]. Universidade Estadual Paulista; 2016. Available from: http://hdl.handle.net/11449/143843

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

29. Rabi, Seyed rabi. MULTI-STEP INHIBITION EXPLAINS HIV-1 PROTEASE INHIBITOR PHARMACODYNAMICS AND RESISTANCE.

Degree: 2014, Johns Hopkins University

URL: http://jhir.library.jhu.edu/handle/1774.2/36941

► HIV-1 protease inhibitors (PIs) are among the most effective antiretroviral drugs due to highly cooperative dose-response curves that are not explained by current pharmacodynamic theory.… (more)

Subjects/Keywords: HIV-1; Protease Inhibitor; multi-step; pharmacodynamics; dose-response curves

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APA (6^th Edition):

Rabi, S. r. (2014). MULTI-STEP INHIBITION EXPLAINS HIV-1 PROTEASE INHIBITOR PHARMACODYNAMICS AND RESISTANCE. (Thesis). Johns Hopkins University. Retrieved from http://jhir.library.jhu.edu/handle/1774.2/36941

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Rabi, Seyed rabi. “MULTI-STEP INHIBITION EXPLAINS HIV-1 PROTEASE INHIBITOR PHARMACODYNAMICS AND RESISTANCE.” 2014. Thesis, Johns Hopkins University. Accessed February 27, 2021. http://jhir.library.jhu.edu/handle/1774.2/36941.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Rabi, Seyed rabi. “MULTI-STEP INHIBITION EXPLAINS HIV-1 PROTEASE INHIBITOR PHARMACODYNAMICS AND RESISTANCE.” 2014. Web. 27 Feb 2021.

Vancouver:

Rabi Sr. MULTI-STEP INHIBITION EXPLAINS HIV-1 PROTEASE INHIBITOR PHARMACODYNAMICS AND RESISTANCE. [Internet] [Thesis]. Johns Hopkins University; 2014. [cited 2021 Feb 27]. Available from: http://jhir.library.jhu.edu/handle/1774.2/36941.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Rabi Sr. MULTI-STEP INHIBITION EXPLAINS HIV-1 PROTEASE INHIBITOR PHARMACODYNAMICS AND RESISTANCE. [Thesis]. Johns Hopkins University; 2014. Available from: http://jhir.library.jhu.edu/handle/1774.2/36941

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Michigan

30. Lau, Henry San Heng. The Pharmacokinetics And Pharmacodynamics Of Bumetanide (diuretics).

Degree: PhD, Pure Sciences, 1985, University of Michigan

URL: http://hdl.handle.net/2027.42/127872

► Bumetanide is a potent loop diuretic that acts at the thick ascending limb of the loop of Henle where it inhibits solute reabsorption. Since bumetanide… (more)

▼ Bumetanide is a potent loop diuretic that acts at the thick ascending limb of the loop of Henle where it inhibits solute reabsorption. Since bumetanide is highly bound to proteins, the drug gains access to the kidney lumen predominantly at the pars recta of the proximal tubule via the nonspecific organic acid secretory pathway. As a result, any drug (e.g. probenecid) or disease state that might alter the amount of bumetanide reaching its site of action can modify the natriuretic and diuretic effects of the drug. The pharmacokinetics and pharmacodynamics of an i.v. injection of bumetanide, before and after probenecid pretreatment in four mongrel dogs were investigated. Sodium excretion was better correlated with the urinary excretion rate of bumetanide than with the plasma concentration of the drug. In addition, the results from steady-state experiments suggested that bumetanide exerts its pharmacodynamic responses from the luminal surface of the nephron and that secretion of bumetanide into the lumen at the proximal tubule is a prerequisite for the pharmacodynamics of the drug. Indomethacin, a prostaglandin synthetase inhibitor, has been shown to decrease the cumulative response to bumetanide. However, indomethacin can potentially attenuate the dynamic responses by competing with bumetanide for active secretion. The results from studying the dynamics and kinetics of an i.v. injection of bumetanide, before and after indomethacin pretreatment in four mongrel dogs, indicated that indomethacin diminishes the response to bumetanide via prostaglandin inhibition and not by a pharmacokinetic interaction. The kinetics, dynamics, and bioavailability of bumetanide were investigated in six chronic renal failure patients and four healthy subjects following a 5 mg intravenous and oral dose. The bioavailability of bumetanide in both groups was approximately 65-70%. The cumulative pharmacodynamic effects were essentially equivalent between oral and intravenous treatments in each group despite a smaller amount of drug being delivered to the site of action after oral administration. Thus it appeas that aside from the faster onset of action to an intravenous route of bumetanide, the oral route is as effective in producing a significant cumulative natriuresis and diuresis.

Subjects/Keywords: Bumetanide; Diuretics; Pharmacodynamics; Pharmacokinetics

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Lau, H. S. H. (1985). The Pharmacokinetics And Pharmacodynamics Of Bumetanide (diuretics). (Doctoral Dissertation). University of Michigan. Retrieved from http://hdl.handle.net/2027.42/127872

Chicago Manual of Style (16^th Edition):

Lau, Henry San Heng. “The Pharmacokinetics And Pharmacodynamics Of Bumetanide (diuretics).” 1985. Doctoral Dissertation, University of Michigan. Accessed February 27, 2021. http://hdl.handle.net/2027.42/127872.

MLA Handbook (7^th Edition):

Lau, Henry San Heng. “The Pharmacokinetics And Pharmacodynamics Of Bumetanide (diuretics).” 1985. Web. 27 Feb 2021.

Vancouver:

Lau HSH. The Pharmacokinetics And Pharmacodynamics Of Bumetanide (diuretics). [Internet] [Doctoral dissertation]. University of Michigan; 1985. [cited 2021 Feb 27]. Available from: http://hdl.handle.net/2027.42/127872.

Council of Science Editors:

Lau HSH. The Pharmacokinetics And Pharmacodynamics Of Bumetanide (diuretics). [Doctoral Dissertation]. University of Michigan; 1985. Available from: http://hdl.handle.net/2027.42/127872

Open Access Theses and Dissertations