subject:(pharmacodynamics)

University of Gothenburg / Göteborgs Universitet

1. Friberg Hietala, Sofia. Clinical pharmacokinetics and pharmacodynamics of antimalarial combination therapy.

Degree: 2009, University of Gothenburg / Göteborgs Universitet

URL: http://hdl.handle.net/2077/19644

► In the face of growing drug resistance, the World Health Organization (WHO) has issued recommendations strongly encouraging the use of combination therapies to combat uncomplicated… (more)

▼ In the face of growing drug resistance, the World Health Organization (WHO) has issued recommendations strongly encouraging the use of combination therapies to combat uncomplicated malaria. Amongst the most effective treatments are those combining an artemisinin derivative with a longer acting component such as amodiaquine, lumefantrine or piperaquine. Despite the widespread use of these treatments there is a lack of understanding regarding both pharmacokinetics and pharmacodynamics of the combinations, particularly in pediatric patients. The aim of this thesis was to describe how the dosing of antimalarials during combination therapy correlates with the outcome of treatment and to investigate factors that may influence this relationship. In order to evaluate the pharmacokinetics and pharmacodynamics of the combinations artesunate + amodiaquine and artemether + lumefantrine in pediatric patients, a group particularly vulnerable to malaria, studies were conducted during the implementation of these new treatment strategies in Tanzania. The population approach to analysing the pharmacokinetics and pharmacodynamics was used in these studies. This method allows the determination of the typical values of pharmacokinetic and pharmacodynamic parameters, as well as the description of the variability in these estimates in the population, from sparse data. Importantly, the method also allows the investigation of how covariates, such as demographics (weight, age) or food intake influences pharmacokinetics and/or pharmacodynamics. An in vitro study was conducted to characterize the plasma protein binding of amodiaquine and its primary metabolite N-desethylamodiaquine. The influence of concomitant intake of a typical Vietnamese meal on the absorption of piperaquine was investigated in healthy subjects. There was a significant, albeit weak, correlation between the clinical outcome of the combination amodiaquine+artesunate and exposure to N-desethylamodiaquine. Amodiaquine and N-desethylamodiaquine were both shown to be extensively bound to plasma proteins in vitro, which may explain the difficulty in establishing a good concentration-effect relationship from total N-desethylamodiaquine concentrations. The proposed semi-mechanistic model of parasite dynamics adequately described the effect of artemether and its active metabolite DHA on the parasite density in malaria patients, with predicted median parasite clearance time corresponding well with the observed. To make full use of the model, however, stage-specific parasite counts should be obtained both prior to, and during, drug treatment. There was no significant impact on the exposure to piperaquine due to concomitant intake of a relatively low-fat meal. The 20-fold range in exposure in both fed and fasting subjects suggests that there are other factors contributing significantly to interindividual differences in piperaquine pharmacokinetics.

Subjects/Keywords: pharmacokinetics; pharmacodynamics; antimalarials; artemisinins

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

APA (6^th Edition):

Friberg Hietala, S. (2009). Clinical pharmacokinetics and pharmacodynamics of antimalarial combination therapy. (Thesis). University of Gothenburg / Göteborgs Universitet. Retrieved from http://hdl.handle.net/2077/19644

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):

Friberg Hietala, Sofia. “Clinical pharmacokinetics and pharmacodynamics of antimalarial combination therapy.” 2009. Thesis, University of Gothenburg / Göteborgs Universitet. Accessed October 19, 2019. http://hdl.handle.net/2077/19644.

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

MLA Handbook (7^th Edition):

Friberg Hietala, Sofia. “Clinical pharmacokinetics and pharmacodynamics of antimalarial combination therapy.” 2009. Web. 19 Oct 2019.

Vancouver:

Friberg Hietala S. Clinical pharmacokinetics and pharmacodynamics of antimalarial combination therapy. [Internet] [Thesis]. University of Gothenburg / Göteborgs Universitet; 2009. [cited 2019 Oct 19]. Available from: http://hdl.handle.net/2077/19644.

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

Council of Science Editors:

Friberg Hietala S. Clinical pharmacokinetics and pharmacodynamics of antimalarial combination therapy. [Thesis]. University of Gothenburg / Göteborgs Universitet; 2009. Available from: http://hdl.handle.net/2077/19644

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

University of Gothenburg / Göteborgs Universitet

2. 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 October 19, 2019. 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. 19 Oct 2019.

Vancouver:

Henning, Matts 1. Studies on the mode of action of î-methyldopa. [Internet] [Thesis]. University of Gothenburg / Göteborgs Universitet; 1969. [cited 2019 Oct 19]. 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 Manchester

3. 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

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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 October 19, 2019. 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. 19 Oct 2019.

Vancouver:

Jeans AR. The pharmacodynamics of antifungal agents against Aspergillus. [Internet] [Doctoral dissertation]. University of Manchester; 2013. [cited 2019 Oct 19]. 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 Manchester

4. 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

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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 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 October 19, 2019. 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. 19 Oct 2019.

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 2019 Oct 19]. 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

5. 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

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 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 October 19, 2019. 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. 19 Oct 2019.

Vancouver:

Jeans AR. The Pharmacodynamics of Antifungal Agents Against Aspergillus. [Internet] [Doctoral dissertation]. University of Manchester; 2013. [cited 2019 Oct 19]. 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

6. 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 October 19, 2019. 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. 19 Oct 2019.

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 2019 Oct 19]. 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

7. 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 October 19, 2019. 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. 19 Oct 2019.

Vancouver:

Licari G. The stereoselective pharmacodynamics of the enantiomers of perhexiline. [Internet] [Thesis]. University of Adelaide; 2013. [cited 2019 Oct 19]. 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

Washington State University

8. [No author]. Analytical Method Development, Pharmacokinetics, and Pharmacodynamics of Selected Polyphenols .

Degree: 2010, Washington State University

URL: http://hdl.handle.net/2376/2780

► Novel analytical methods were developed and validated according to the International Conference on Harmonization guidelines using high-performance liquid chromatography (HPLC) with ultraviolet (UV) and/or electrospray… (more)

▼ Novel analytical methods were developed and validated according to the International Conference on Harmonization guidelines using high-performance liquid chromatography (HPLC) with ultraviolet (UV) and/or electrospray ionization (ESI) – mass spectrometry (MS) for the separation, isolation, and detection of sakuranetin, β-glucogallin, gallic acid, oxyresveratrol, and 3’–hydroxypterostilbene in biological matrices. The selected polyphenols were quantified in samples from rice, apples, oranges, grapefruit juice, matico, and/or Indian gooseberry through the application of the developed analytical methods. As these polyphenols are distributed in a variety of botanicals and are widely consumed as plants and nutraceuticals, the pharmacokinetics and pharmacodynamics were studied.These methods were applied to fecal, serum, and urine samples obtained from a rat model to characterize the pharmacokinetics of the selected polyphenols and major metabolites after intravenous or oral administration. The pharmacokinetic parameters of each polyphenol were delineated for the first time. These studies uniformly demonstrated poor bioavailability, rapid metabolism to glucuroconjugates and elimination of the selected polyphenols via renal and non-renal pathways. The clinical pharmacokinetics and attempts to increase bioavailability remain to be evaluated.Effects of sakuranetin, β–glucogallin, gallic acid, oxyresveratrol, and 3’–hydroxypterostilbene in in–vitro and/or in–vivo models of adipogenesis, oxidative stress, inflammation and pain, histone deacetylase / sirtuin 1 modulation, and cell proliferation were examined. In these studies sakuranetin, gallic acid, oxyresveratrol, and 3’–hydroxypterostilbene demonstrated anti’adipogenic properties. All polyphenols studied maintained their ability to scavenge free radicals as anti’oxidants. All of the selected polyphenols were effective in reducing cyclooygenase’1 and’2 activities. Racemic sakuranetin and 3’–hydroxypterostilbene was able to inhibit the synthesis of prostaglandins. β’glucogallin, gallic acid, and 3’–hydroxypterostilbene also demonstrated anti-nociceptive activity. The study of polyphenols may lead to the alternative treatments for inflammation and pain. Although the selected polyphenols were not potent anti’proliferative agents in the cancer cell lines examined as determined using the Alamar blue method, their ability to inhibit histone deacetylase activity was evident. Given their ability to inhibit HDAC the utility of polyphenols as mood stabilizers or anti’epilectics should be studied. Advisors/Committee Members: Davies, Neal M (advisor).

Subjects/Keywords: analytical method; pharmacodynamics; pharmacokinetics

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

APA (6^th Edition):

author], [. (2010). Analytical Method Development, Pharmacokinetics, and Pharmacodynamics of Selected Polyphenols . (Thesis). Washington State University. Retrieved from http://hdl.handle.net/2376/2780

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):

author], [No. “Analytical Method Development, Pharmacokinetics, and Pharmacodynamics of Selected Polyphenols .” 2010. Thesis, Washington State University. Accessed October 19, 2019. http://hdl.handle.net/2376/2780.

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

MLA Handbook (7^th Edition):

author], [No. “Analytical Method Development, Pharmacokinetics, and Pharmacodynamics of Selected Polyphenols .” 2010. Web. 19 Oct 2019.

Vancouver:

author] [. Analytical Method Development, Pharmacokinetics, and Pharmacodynamics of Selected Polyphenols . [Internet] [Thesis]. Washington State University; 2010. [cited 2019 Oct 19]. Available from: http://hdl.handle.net/2376/2780.

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

Council of Science Editors:

author] [. Analytical Method Development, Pharmacokinetics, and Pharmacodynamics of Selected Polyphenols . [Thesis]. Washington State University; 2010. Available from: http://hdl.handle.net/2376/2780

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

Drexel University

9. Chen, Wendi. Pharmacokinetic and pharmacodynamic modeling of erythropoiesis stimulating agents in rats.

Degree: 2010, Drexel University

URL: http://hdl.handle.net/1860/3459

►

Erythropoiesis is a process by which red blood cells are produced in the bone marrow. Disruption of this process can lead to anemia. Erythropoiesis stimulating… (more)

▼

Erythropoiesis is a process by which red blood cells are produced in the bone marrow. Disruption of this process can lead to anemia. Erythropoiesis stimulating agents (ESAs), such as epoetin- and darbepoetin- , have been developed to treat anemia. CNTO 530 is a novel ESA that has a longer terminal half-life than either epoetin- or darbepoetin- . As these ESAs all activate erythropoietin receptor (EPO-R), we hypothesize that any di erences in the pharmacologic activity are solely dependent on their pharmacokinetic properties. To test this hypothesis, we proposed a new Pharmacokinetic/Pharmacodynamic (PK/PD) model to account for the pharmacological response. Rats received a single subcutaneous (s.c.) dose of the ESA and reticulocyte (RET) counts, red blood cell (RBC) counts and hemoglobin (HGB) levels were measured for up to 72 days (1728 hours) post-dosing. Various dosage levels were studied for each drug. A new indirect response model with multiple regulatory e ects was used to characterize the PD responses and a linear two-compartmental model was used to characterize the PK responses. All three agents caused a dose responsive increase in RET, RBC and HGB. Compared to epoetin- and darbepoetin- , CNTO 530 caused a longer-lived increase in these parameters. A single PK/PD model could represent all three agents. However, when comparing among the erythropoietic responses to doses that increased RBC, the coe cients of the model indicate that despite having a lower potency, CNTO 530 caused a more rapid mobilization of RET. The results of the PK/PD modeling suggest that CNTO 530 stimulates erythropoiesis in a similar fashion to epoetin- and darbepoetin- and that the PK properties of an ESA are the most important factor in determining e cacy. In addition, dose threshold is an important factor we need to consider in designing the PK/PD model. Understanding dose threshold of a drug aids in determining appropriate dose levels and, therefore, helps diminish side e ects of the compound and reduces treatment costs. Many studies have focused on non-quantitative analysis of drug dose threshold, which can be biased by various factors. Aiming for quantitative analysis of this parameter, we proposed two statistical methods to determine dose threshold of a drug and applied them to CNTO 530.

Ph.D., Electrical Engineering – Drexel University, 2010

Advisors/Committee Members: Hrebien, Leonid, 1949-, Kam, Moshe.

Subjects/Keywords: Electric engineering; Pharmacokinetics; Pharmacodynamics

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

APA (6^th Edition):

Chen, W. (2010). Pharmacokinetic and pharmacodynamic modeling of erythropoiesis stimulating agents in rats. (Thesis). Drexel University. Retrieved from http://hdl.handle.net/1860/3459

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):

Chen, Wendi. “Pharmacokinetic and pharmacodynamic modeling of erythropoiesis stimulating agents in rats.” 2010. Thesis, Drexel University. Accessed October 19, 2019. http://hdl.handle.net/1860/3459.

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

MLA Handbook (7^th Edition):

Chen, Wendi. “Pharmacokinetic and pharmacodynamic modeling of erythropoiesis stimulating agents in rats.” 2010. Web. 19 Oct 2019.

Vancouver:

Chen W. Pharmacokinetic and pharmacodynamic modeling of erythropoiesis stimulating agents in rats. [Internet] [Thesis]. Drexel University; 2010. [cited 2019 Oct 19]. Available from: http://hdl.handle.net/1860/3459.

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

Council of Science Editors:

Chen W. Pharmacokinetic and pharmacodynamic modeling of erythropoiesis stimulating agents in rats. [Thesis]. Drexel University; 2010. Available from: http://hdl.handle.net/1860/3459

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 October 19, 2019. 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. 19 Oct 2019.

Vancouver:

Keizer RJ. Pharmacometrics in early clinical drug development. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2010. [cited 2019 Oct 19]. 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

Temple University

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

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 October 19, 2019. 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. 19 Oct 2019.

Vancouver:

Wang S. DRUG DEVELOPMENT OF TARGETED ANTICANCER DRUGS BASED ON PK/PD INVESTIGATIONS. [Internet] [Doctoral dissertation]. Temple University; 2008. [cited 2019 Oct 19]. 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 Otago

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

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 October 19, 2019. http://hdl.handle.net/10523/4398.

MLA Handbook (7^th Edition):

Wright, Daniel Frank. “Model-based Drug Dosing .” 2013. Web. 19 Oct 2019.

Vancouver:

Wright DF. Model-based Drug Dosing . [Internet] [Doctoral dissertation]. University of Otago; 2013. [cited 2019 Oct 19]. 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

University of Gothenburg / Göteborgs Universitet

13. Röshammar, Daniel. Applied Population Pharmacokinetic/ Pharmacodynamic Modeling of Antiretroviral and Antimalarial Drug Therapy.

Degree: 2009, University of Gothenburg / Göteborgs Universitet

URL: http://hdl.handle.net/2077/19044

► HIV/AIDS and malaria are two major global infectious diseases. Although better drugs against these conditions are becoming more available, dosages may not always be optimal… (more)

▼ HIV/AIDS and malaria are two major global infectious diseases. Although better drugs against these conditions are becoming more available, dosages may not always be optimal with respect to effectiveness, safety, cost or convenience of administration. This thesis aims to quantitate the pharmacological relationship between dosing history, sources of variation between individuals, drug exposure and response to selected antiretroviral and antimalarial regimens. Pharmacometric, i.e. pharmaco-statistical, models were fitted to observed data from five clinical studies, using the nonmem software. Several polymorphic genes coding for drug metabolizing enzymes and transporters were found to have impact on the disposition of the non-nucleoside reverse transcriptase inhibitor efavirenz in healthy Ugandan subjects after single dose administration. Moreover, using simulation it was demonstrated that a 200 mg dose reduction in Zimbabwean HIV-patients with genetically decreased metabolic capacity would maintain efavirenz exposure within the therapeutic range during repeated administration. In a typical clinical trial large amounts of drug response data are collected. However, usually only limited amounts of the recorded data are actually used for investigating differences between regimens. Herein, a drug-disease model was developed to describe the time-course of repeatedly measured HIV-RNA levels in Scandinavian patients randomized to one of three commonly prescribed antiretroviral regimens. The initial analysis showed that an efavirenz-containing regimen appeared to be more efficacious compared to two protease inhibitor-containing regimens. Antimalarial artemisinin-based combination therapy bears many resemblances to antiretroviral treatment. The drugs exhibit variable and complex pharmacokinetics and the diseases themselves bring reasonable possibilities for pharmacodynamic assessment. Auto-induction of drug metabolism was described after multiple dosing with artemisinin in Vietnamese patients. The frequency of recrudescent malaria infection was as high as 37% but could not directly be linked to low artemisinin exposure. The elimination half-life of piperaquine, a suitable partner drug for artemisinin-based combination treatment, was estimated to 12 days with large between-subject variability. The thesis demonstrates the utility of pharmacometric methodology in the analysis of clinical data originating from high-income countries as well as resource-limited settings. Ultimately it can be a tool for decision analysis and policy making.

Subjects/Keywords: HIV; malaria; pharmacokinetics; pharmacodynamics; pharmacometrics; NONMEM

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APA (6^th Edition):

Röshammar, D. (2009). Applied Population Pharmacokinetic/ Pharmacodynamic Modeling of Antiretroviral and Antimalarial Drug Therapy. (Thesis). University of Gothenburg / Göteborgs Universitet. Retrieved from http://hdl.handle.net/2077/19044

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):

Röshammar, Daniel. “Applied Population Pharmacokinetic/ Pharmacodynamic Modeling of Antiretroviral and Antimalarial Drug Therapy.” 2009. Thesis, University of Gothenburg / Göteborgs Universitet. Accessed October 19, 2019. http://hdl.handle.net/2077/19044.

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

MLA Handbook (7^th Edition):

Röshammar, Daniel. “Applied Population Pharmacokinetic/ Pharmacodynamic Modeling of Antiretroviral and Antimalarial Drug Therapy.” 2009. Web. 19 Oct 2019.

Vancouver:

Röshammar D. Applied Population Pharmacokinetic/ Pharmacodynamic Modeling of Antiretroviral and Antimalarial Drug Therapy. [Internet] [Thesis]. University of Gothenburg / Göteborgs Universitet; 2009. [cited 2019 Oct 19]. Available from: http://hdl.handle.net/2077/19044.

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

Council of Science Editors:

Röshammar D. Applied Population Pharmacokinetic/ Pharmacodynamic Modeling of Antiretroviral and Antimalarial Drug Therapy. [Thesis]. University of Gothenburg / Göteborgs Universitet; 2009. Available from: http://hdl.handle.net/2077/19044

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

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/3831

► 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/3831

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 October 19, 2019. http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/637770/rec/3831.

MLA Handbook (7^th Edition):

Chen, Xiaoying. “Linkers in transferrin fusion proteins: effects on pharmacokinetics and pharmacodynamics.” 2011. Web. 19 Oct 2019.

Vancouver:

Chen X. Linkers in transferrin fusion proteins: effects on pharmacokinetics and pharmacodynamics. [Internet] [Doctoral dissertation]. University of Southern California; 2011. [cited 2019 Oct 19]. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/637770/rec/3831.

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/3831

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 October 19, 2019. 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. 19 Oct 2019.

Vancouver:

Kim HY. Personalised Medicine in the Treatment of Cancer . [Internet] [Thesis]. University of Sydney; 2018. [cited 2019 Oct 19]. 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

University of Gothenburg / Göteborgs Universitet

16. 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 October 19, 2019. 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. 19 Oct 2019.

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 2019 Oct 19]. 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

17. 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 October 19, 2019. 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. 19 Oct 2019.

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 2019 Oct 19]. 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

18. 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 October 19, 2019. 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. 19 Oct 2019.

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 2019 Oct 19]. 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

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

Degree: 2010, University Utrecht

URL: http://dspace.library.uu.nl/handle/1874/179786 ; URN:NBN:NL:UI:10-1874-179786 ; urn:isbn:978-90-9025632-0 ; URN:NBN:NL:UI:10-1874-179786 ; http://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 (6^th Edition):

Keizer, R. J. (2010). Pharmacometrics in early clinical drug development. (Doctoral Dissertation). University Utrecht. Retrieved from http://dspace.library.uu.nl/handle/1874/179786 ; URN:NBN:NL:UI:10-1874-179786 ; urn:isbn:978-90-9025632-0 ; URN:NBN:NL:UI:10-1874-179786 ; http://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 October 19, 2019. http://dspace.library.uu.nl/handle/1874/179786 ; URN:NBN:NL:UI:10-1874-179786 ; urn:isbn:978-90-9025632-0 ; URN:NBN:NL:UI:10-1874-179786 ; http://dspace.library.uu.nl/handle/1874/179786.

MLA Handbook (7^th Edition):

Keizer, R J. “Pharmacometrics in early clinical drug development.” 2010. Web. 19 Oct 2019.

Vancouver:

Keizer RJ. Pharmacometrics in early clinical drug development. [Internet] [Doctoral dissertation]. University Utrecht; 2010. [cited 2019 Oct 19]. Available from: http://dspace.library.uu.nl/handle/1874/179786 ; URN:NBN:NL:UI:10-1874-179786 ; urn:isbn:978-90-9025632-0 ; URN:NBN:NL:UI:10-1874-179786 ; http://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: http://dspace.library.uu.nl/handle/1874/179786 ; URN:NBN:NL:UI:10-1874-179786 ; urn:isbn:978-90-9025632-0 ; URN:NBN:NL:UI:10-1874-179786 ; http://dspace.library.uu.nl/handle/1874/179786

University of Utah

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

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 October 19, 2019. 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. 19 Oct 2019.

Vancouver:

LaPierre CD. Identification of optimal dosing regimens for procedures requiring esophageal instrumentation through multiobjective optimization. [Internet] [Doctoral dissertation]. University of Utah; 2010. [cited 2019 Oct 19]. 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

21. 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 October 19, 2019. 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. 19 Oct 2019.

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 2019 Oct 19]. 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

Aristotle University Of Thessaloniki (AUTH); Αριστοτέλειο Πανεπιστήμιο Θεσσαλονίκης (ΑΠΘ)

22. Δελής, Γεώργιος. Φαρμακοκινητική / φαρμακοδυναμική συσχέτιση της αμοξικιλλίνης στο πρόβατο.

Degree: 2009, Aristotle University Of Thessaloniki (AUTH); Αριστοτέλειο Πανεπιστήμιο Θεσσαλονίκης (ΑΠΘ)

URL: http://hdl.handle.net/10442/hedi/19233

►

Amoxicillin (AMX), a semi-synthetic, broad-spectrum α-amino-p-hydroxybenzylpenicillin has been long used in veterinary medical practice for the treatment of bacterial respiratory, urinary, gastrointestinal, dermal, dental and… (more)

▼

Amoxicillin (AMX), a semi-synthetic, broad-spectrum α-amino-p-hydroxybenzylpenicillin has been long used in veterinary medical practice for the treatment of bacterial respiratory, urinary, gastrointestinal, dermal, dental and other infections. In sheep therapeutics, AMX is typically administered intramuscularly as its trihydrate form, contained in conventional or long-acting formulations (suspensions). Although published pharmacokinetic studies of AMX in several animal species and humans generally describe a highly variable distribution in several body organs and tissues (i.e. good penetration in kidneys, liver, lungs, muscles, peritoneal, pleural and synovial fluids, etc. versus reduced penetration in the central nervous system, aqueous humour, lacrimal fluid, sweat, saliva and milk), no relevant data exist in sheep. A complete dearth of data is also observed concerning the influence of the formulation type and the injection site on AMX absorption and its pharmacokinetic behavior, after intramuscular administration. Antimicrobials of the β-lactam class are generally described as agents displaying a time-dependent bactericidal activity, the in vivo efficacy of which relies on the achieved value of the therapeutic time (T>MIC) index, defined as the time, expressed as a percentage of the 24 hours post administration, during which drug concentrations exceed the minimal inhibitory concentration (MIC) against the targeted bacterial pathogen. It has been proposed that maximization of AMX bactericidal effect also requires, on occasion, a rise of its levels up to 5 ? MIC; however, such an assumption is yet to be confirmed for pathogen microorganisms isolated from clinical cases in sheep. The present doctoral thesis has been conducted in order to study a) the pharmacokinetics and distribution of AMX in sheep, with use of the tissue cage model, after its intravenous and intramuscular administrations, b) its pharmacodynamics against pathogen microorganisms, responsible for causing severe infections in the specific animal species, and c) the correlation of pharmacokinetic and pharmacodynamic data for the evaluation of the drug’s therapeutic efficacy.

Η αμοξικιλλίνη (ΑΜΧ), μία ημισυνθετική, ευρέος φάσματος α-αμινο-p- υδροξυβενζυλοπενικιλλίνη, χρησιμοποιείται επί μακρόν στην κτηνιατρική πράξη για τη θεραπεία βακτηριακών λοιμώξεων του αναπνευστικού και του ουροποιητικού συστήματος, καθώς και του γαστρεντερικού σωλήνα, του δέρματος, των οδόντων κ.λπ. Στη θεραπευτική του προβάτου χορηγείται κατά κανόνα ενδομυϊκώς, υπό την τριυδρική μορφή της, η οποία και περιέχεται σε ιδιοσκευάσματα (εναιωρήματα) συμβατικής ή μακράς διάρκειας δράσης. Αν και οι μέχρι σήμερα δημοσιευμένες μελέτες της φαρμακοκινητικής της ΑΜΧ σε διάφορα είδη ζώων και στον άνθρωπο περιγράφουν, γενικά, μία υψηλής παραλλακτικότητας κατανομή της στα διάφορα όργανα και ιστούς του σώματος (π.χ. καλή διείσδυση σε νεφρούς, ήπαρ, πνεύμονες, μύς, περιτοναϊκό υγρό, πλευρικό υγρό, αρθρικό υγρό κ.λπ. και μειωμένη διείσδυση σε κεντρικό νευρικό σύστημα, υδατοειδές υγρό, δάκρυα,…

Subjects/Keywords: Αμοξικιλλίνη; Φαρμακοκινητική; Φαρμακοδυναμική; Συσχέτιση; Πρόβατα; Amoxicillin; Pharmacokinetics; Pharmacodynamics; Correlation; Sheeps

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

APA (6^th Edition):

Δελής, . �. (2009). Φαρμακοκινητική / φαρμακοδυναμική συσχέτιση της αμοξικιλλίνης στο πρόβατο. (Thesis). Aristotle University Of Thessaloniki (AUTH); Αριστοτέλειο Πανεπιστήμιο Θεσσαλονίκης (ΑΠΘ). Retrieved from http://hdl.handle.net/10442/hedi/19233

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):

Δελής, Γεώργιος. “Φαρμακοκινητική / φαρμακοδυναμική συσχέτιση της αμοξικιλλίνης στο πρόβατο.” 2009. Thesis, Aristotle University Of Thessaloniki (AUTH); Αριστοτέλειο Πανεπιστήμιο Θεσσαλονίκης (ΑΠΘ). Accessed October 19, 2019. http://hdl.handle.net/10442/hedi/19233.

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

MLA Handbook (7^th Edition):

Δελής, Γεώργιος. “Φαρμακοκινητική / φαρμακοδυναμική συσχέτιση της αμοξικιλλίνης στο πρόβατο.” 2009. Web. 19 Oct 2019.

Vancouver:

Δελής �. Φαρμακοκινητική / φαρμακοδυναμική συσχέτιση της αμοξικιλλίνης στο πρόβατο. [Internet] [Thesis]. Aristotle University Of Thessaloniki (AUTH); Αριστοτέλειο Πανεπιστήμιο Θεσσαλονίκης (ΑΠΘ); 2009. [cited 2019 Oct 19]. Available from: http://hdl.handle.net/10442/hedi/19233.

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

Council of Science Editors:

Δελής �. Φαρμακοκινητική / φαρμακοδυναμική συσχέτιση της αμοξικιλλίνης στο πρόβατο. [Thesis]. Aristotle University Of Thessaloniki (AUTH); Αριστοτέλειο Πανεπιστήμιο Θεσσαλονίκης (ΑΠΘ); 2009. Available from: http://hdl.handle.net/10442/hedi/19233

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

University of Kansas

23. Thomas, Sara R. Investigation of Microdialysis Sampling to Monitor Pharmacodynamics.

Degree: PhD, Chemistry, 2014, University of Kansas

URL: http://hdl.handle.net/1808/19604

► Microdialysis sampling is a technique commonly used to monitor a variety of processes in a tissue-targeted fashion. This sampling technique has several advantages over other… (more)

▼ Microdialysis sampling is a technique commonly used to monitor a variety of processes in a tissue-targeted fashion. This sampling technique has several advantages over other methods since it allows continuous sampling throughout the entire experiment. Because microdialysis can be implanted in virtually any tissue, the application of the microdialysis sampling technique can be applied in many areas, including monitoring enzyme activity mechanisms or monitoring the effects of chemotherapy agents on brain activity. To expand the application of microdialysis sampling, two different enzymes were monitored and tested with this tissue-specific sampling technique. The use of microdialysis sampling to monitor the activity of 11beta-HSD1 in vitro and in vivo would increase the throughput for screening novel inhibitors. Microdialysis sampling was successful in monitoring the conversion of cortisone to cortisol in vitro human microsome experiments, but not so in rat microsome in vitro or in vivo experiments. This was because rat enzymes generate a different metabolite profile than humans. In a separate study, microdialysis was used to monitor the production of cGMP by the enzyme activation of GC-C in the colon submucosa. The location of the microdialysis probe was verified by comparing the concentration of cGMP in a probe implanted in the submucosa and lumen microdialysis probe. These results indicated a clear correlation with probe placement. Upon the activation of a GC-C agonist, a consistent increase in cGMP levels was seen in the submucosa probe. This allows further determination of the mechanisms responsible for pain reduction upon the administration of GC-C agonists in the submucosa, which has not been performed before due to the inability of obtaining this tissue using conventional methods. The second studies utilized microdialysis sampling to continuously monitor neurotransmitters and an oxidative stress biomarker (MDA) before, during and after the administration of anticancer compounds. Both short- and long-term studies were performed. Initial studies monitored the direct effects of these chemotherapy compounds in short-term experiments using direct perfusion. An increase in glutamate and GABA was seen upon the administration of doxorubicin and cyclophosphamide through the microdialysis probe. This demonstrated the toxicity of these compounds on brain activity. These anticancer compounds were then administered in long-term experiments to obtain a complete time-profile of the changes on several neurotransmitters and MDA upon chemotherapy administration. A detectable change was not seen in the amino acid neurotransmitters or MDA in the samples analyzed. An increase was seen in glutamate with IP administration; however this was also seen in the control rat. To alleviate an increase in glutamate from handling, several intravenous cannulations were attempted and no difference was seen in any of these experiments. During these experiments, the longest microdialysis studies were performed, to the best of our knowledge, and the… Advisors/Committee Members: Lunte, Craig E (advisor), Lunte, Susan M (cmtemember), Johnson, Michael A (cmtemember), Carlson, Robert G (cmtemember), Aldrich, Jane V (cmtemember).

Subjects/Keywords: Chemistry; Chemobrain; Enzyme Activity; in vivo; Microdialysis; Pharmacodynamics; tissue-targeted sampling

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APA (6^th Edition):

Thomas, S. R. (2014). Investigation of Microdialysis Sampling to Monitor Pharmacodynamics. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/19604

Chicago Manual of Style (16^th Edition):

Thomas, Sara R. “Investigation of Microdialysis Sampling to Monitor Pharmacodynamics.” 2014. Doctoral Dissertation, University of Kansas. Accessed October 19, 2019. http://hdl.handle.net/1808/19604.

MLA Handbook (7^th Edition):

Thomas, Sara R. “Investigation of Microdialysis Sampling to Monitor Pharmacodynamics.” 2014. Web. 19 Oct 2019.

Vancouver:

Thomas SR. Investigation of Microdialysis Sampling to Monitor Pharmacodynamics. [Internet] [Doctoral dissertation]. University of Kansas; 2014. [cited 2019 Oct 19]. Available from: http://hdl.handle.net/1808/19604.

Council of Science Editors:

Thomas SR. Investigation of Microdialysis Sampling to Monitor Pharmacodynamics. [Doctoral Dissertation]. University of Kansas; 2014. Available from: http://hdl.handle.net/1808/19604

Brunel University

24. Giltrow, Emma. Pharmaceuticals in the aquatic environment : β-blockers as a case study.

Degree: 2008, Brunel University

URL: http://bura.brunel.ac.uk/handle/2438/5186 ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.488679

► The presence of many human pharmaceuticals in the aquatic environment is now a worldwide concern and yet little is known of the chronic effects that… (more)

Subjects/Keywords: 571.95; Mammalian pharmacodynamics; Propranolol; Adrenergic receptor; Fathead minnows; Fish

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APA (6^th Edition):

Giltrow, E. (2008). Pharmaceuticals in the aquatic environment : β-blockers as a case study. (Doctoral Dissertation). Brunel University. Retrieved from http://bura.brunel.ac.uk/handle/2438/5186 ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.488679

Chicago Manual of Style (16^th Edition):

Giltrow, Emma. “Pharmaceuticals in the aquatic environment : β-blockers as a case study.” 2008. Doctoral Dissertation, Brunel University. Accessed October 19, 2019. http://bura.brunel.ac.uk/handle/2438/5186 ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.488679.

MLA Handbook (7^th Edition):

Giltrow, Emma. “Pharmaceuticals in the aquatic environment : β-blockers as a case study.” 2008. Web. 19 Oct 2019.

Vancouver:

Giltrow E. Pharmaceuticals in the aquatic environment : β-blockers as a case study. [Internet] [Doctoral dissertation]. Brunel University; 2008. [cited 2019 Oct 19]. Available from: http://bura.brunel.ac.uk/handle/2438/5186 ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.488679.

Council of Science Editors:

Giltrow E. Pharmaceuticals in the aquatic environment : β-blockers as a case study. [Doctoral Dissertation]. Brunel University; 2008. Available from: http://bura.brunel.ac.uk/handle/2438/5186 ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.488679

University of Cincinnati

25. Dave, Nimita D. Brain/Brain Tumor Pharmacokinetics and Pharmacodynamics of Letrozole.

Degree: PhD, Pharmacy: Pharmaceutical Sciences/Biopharmaceutics, 2013, University of Cincinnati

URL: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1368013158

► The lack of well-identified targets and limited access of drugs across the blood-brain and blood- tumor barriers are major impediments to the treatment of brain… (more)

▼ The lack of well-identified targets and limited access of drugs across the blood-brain and blood- tumor barriers are major impediments to the treatment of brain tumors. In this study, we investigated the potential role of aromatase (CYP19) as a target for the treatment of CNS malignancies, as well as brain disposition and anti-tumor efficacy of letrozole, an aromatase inhibitor, in Sprague Dawley rats.Cytotoxicity and aromatase activity of letrozole against human glioma cell lines were measured using MTT assay and Enzyme Immunoassay respectively. For brain and brain tumor PK of letrozole, rats with and without orthotopic implantation of C6 glioma received letrozole (4 - 12 mg/kg; i.v.). Dual probe intracerebral microdialysis was performed to determine the unbound extracellular fluid (ECF) letrozole concentrations. Serial ECF and blood samples were simultaneously collected over 8 hrs. µ5;PET/CT imaging was performed using 18F FDG to evaluate changes in active tumor volumes pre- and post-treatment of letrozole. Brain tissues were collected at the end of the experiment for histological evaluations.All glioma cell lines included in this study expressed CYP19 and letrozole exerted marked cytotoxicity against these cells ( IC50s 0.1 -3.5 µ5;M). Normal brain ECF and plasma Cmax and AUC0-8hr increased linearly up to 8mg/kg letrozole dose. However, at higher doses, brain and plasma AUC0-8hr increased non-linearly. The relative brain distribution coefficients, measured as the ratio of the observed AUC in ECF and AUC of unbound letrozole in plasma (AUCecf/AUCp, ub) ranged from 0.31 - 0.98. Furthermore, the tumoral ECF levels of letrozole was 1.5 - 2 fold higher relative to tumor-free region of the brain, resulting in tumoral ECF Cmax values that were 10 and 35-fold higher than the observed IC50 value of 0.1 µM against C6 gliomas cells in culture. µPET/CT imaging showed a marked reduction of active tumor volume (¿ 75-90%) after 8-10 days of letrozole treatment (N=7). Thus, employing multifaceted and cutting edge in vitro and in vivo methods, we conclude: a) aromatase is abundantly expressed in glioma cell lines examined, b) letrozole exerts marked cytotoxicity in these cells presumably due to aromatase inhibition, c) letrozole has selectively higher accumulation in tumoral region of the brain and d) In vivo µPET/CT studies show marked efficacy of letrozole on C6 glioma in a preclinical rat model. Advisors/Committee Members: Desai, Pankaj (Committee Chair).

Subjects/Keywords: Pharmaceuticals; pharmacokinetics; pharmacodynamics; letrozole; brain tumor; preclinical; glioma

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APA (6^th Edition):

Dave, N. D. (2013). Brain/Brain Tumor Pharmacokinetics and Pharmacodynamics of Letrozole. (Doctoral Dissertation). University of Cincinnati. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=ucin1368013158

Chicago Manual of Style (16^th Edition):

Dave, Nimita D. “Brain/Brain Tumor Pharmacokinetics and Pharmacodynamics of Letrozole.” 2013. Doctoral Dissertation, University of Cincinnati. Accessed October 19, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1368013158.

MLA Handbook (7^th Edition):

Dave, Nimita D. “Brain/Brain Tumor Pharmacokinetics and Pharmacodynamics of Letrozole.” 2013. Web. 19 Oct 2019.

Vancouver:

Dave ND. Brain/Brain Tumor Pharmacokinetics and Pharmacodynamics of Letrozole. [Internet] [Doctoral dissertation]. University of Cincinnati; 2013. [cited 2019 Oct 19]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1368013158.

Council of Science Editors:

Dave ND. Brain/Brain Tumor Pharmacokinetics and Pharmacodynamics of Letrozole. [Doctoral Dissertation]. University of Cincinnati; 2013. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1368013158

The Ohio State University

26. Aimiuwu, Josephine Eki. Modulation of Pharmacologic Effects of 5-Azacytidine by Ribonucleotide Reductase Antisense GTI-2040.

Degree: PhD, Pharmacy, 2011, The Ohio State University

URL: http://rave.ohiolink.edu/etdc/view?acc_num=osu1292851882

► Cancer, like most human diseases is complex and the therapeutic approaches available to treat this disease have limited efficacy. Therefore, combination studies of two or… (more)

▼ Cancer, like most human diseases is complex and the therapeutic approaches available to treat this disease have limited efficacy. Therefore, combination studies of two or more anticancer drugs is expected to be essential in achieving a better therapeutic response in patients and may also provide a cure for drug-resistant cancers. Leukemia is a cancer of the blood, which results from an uncontrolled proliferation of white blood cells, thereby inhibiting its functions. Important insights into the pathogenesis of this disease have led to the development of a number of anti-leukemia drugs, including nucleoside analogs and new antisense compounds, that intervene at the level of disease progression. 5-Azacytidine and decitabine are hypomethylating agents recently approved by the U.S Food and Drug Administration for the treatment of Myelodysplastic Syndrome (MDS) and are also in clinical trials for the treatment of hematological malignancies, such as acute myeloid leukemia (AML). These drugs are approved based on their ability to induce DNA demethylation, resulting in reactivation of hypermethylation-associated silencing of tumor suppressor genes. Aracytidine (Ara-C) is another nucleoside drug, widely used as antimetabolite for the treatment of acute myelogenous leukemia. Antisense GTI-2040 is a 20-mer oligonucleotide inhibiting the expression of ribonucleotide reductase subunit M2 (RRM2) mRNA, an enzyme that has been found to be over-expressed in most cancers. In this dissertation, investigations on pharmacodynamic studies of nucleoside analogs in combination with GTI-2040 were carried out. It has been demonstrated that inhibition of cellular RR, which subsequently decreases deoxyribonucleotide triphosphate (dNTP) pools, could enhance the anti-tumor activity of subsequently administered nucleoside analogs. We have in our studies, provided both in vitro and in vivo evidences to support the novel combination treatment of antisense GTI-2040 and 5-azaC, leading to a synergistic effect. In addition, GTI-2040 decreases RRM2 levels, and most notably, we discovered that 5-azaC modulates RRM2 for the first time and this result makes RR a novel target for 5-azaC. In addition, the biomarkers involved in the development of 5-azaC and decitabine (DAC) resistances were assessed in order to elucidate the potential mechanisms that contribute to the induction of resistance in cancer cells. In a phase II evaluation of GTI-2040 in combination with Ara-C in patients with AML at The James Cancer Hospital and Research Institute at The Ohio State University, clinical pharmacokinetic of GTI-2040 and the in vitro-in vivo pharmacodynamic analysis with Ara-C was established to assist in the exploration of their pharmacokinetic-pharmacodynamic (PK-PD) correlations in relation to clinical response. Finally, our studies of GTI-2040, 5-AzaC, DAC and Ara-C provide valuable insights into their clinical development as a single agent or in combination with other drugs. Advisors/Committee Members: Chan, Kenneth (Advisor).

Subjects/Keywords: Pharmaceuticals; preclinical; clinical pharmacokinetics/pharmacodynamics; and drug development

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

APA (6^th Edition):

Aimiuwu, J. E. (2011). Modulation of Pharmacologic Effects of 5-Azacytidine by Ribonucleotide Reductase Antisense GTI-2040. (Doctoral Dissertation). The Ohio State University. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=osu1292851882

Chicago Manual of Style (16^th Edition):

Aimiuwu, Josephine Eki. “Modulation of Pharmacologic Effects of 5-Azacytidine by Ribonucleotide Reductase Antisense GTI-2040.” 2011. Doctoral Dissertation, The Ohio State University. Accessed October 19, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1292851882.

MLA Handbook (7^th Edition):

Aimiuwu, Josephine Eki. “Modulation of Pharmacologic Effects of 5-Azacytidine by Ribonucleotide Reductase Antisense GTI-2040.” 2011. Web. 19 Oct 2019.

Vancouver:

Aimiuwu JE. Modulation of Pharmacologic Effects of 5-Azacytidine by Ribonucleotide Reductase Antisense GTI-2040. [Internet] [Doctoral dissertation]. The Ohio State University; 2011. [cited 2019 Oct 19]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1292851882.

Council of Science Editors:

Aimiuwu JE. Modulation of Pharmacologic Effects of 5-Azacytidine by Ribonucleotide Reductase Antisense GTI-2040. [Doctoral Dissertation]. The Ohio State University; 2011. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1292851882

The Ohio State University

27. Cober, Richard E. Effects of Ivabradine, A New Selective If Current Inhibitor, on Heart Rate in Cats.

Degree: MS, Veterinary Clinical Sciences, 2010, The Ohio State University

URL: http://rave.ohiolink.edu/etdc/view?acc_num=osu1272998433

► Heart rate is one of the main determinants of ischemia, a pathophysiologic characteristic of hypertrophic cardiomyopathy (HCM). Unwanted tachycardia may trigger decompensation in previously asymptomatic… (more)

▼ Heart rate is one of the main determinants of ischemia, a pathophysiologic characteristic of hypertrophic cardiomyopathy (HCM). Unwanted tachycardia may trigger decompensation in previously asymptomatic cats with HCM. Beta blockers are the primary medications used to reduce heart rate in cats, however, side effects or contraindications sometimes limit their use. Ivabradine is a highly selective If current inhibitor. The drug exerts negative chronotropic effects without significant effects on inotropy, lusitropy, or dromotropy in multiple species. Ivabradine, has never been studied in cats. The purpose of this study was to determine an effective oral dose of ivabradine to significantly reduce heart rate in healthy cats. In this single blinded, placebo controlled, randomized, fully-crossed study 8 healthy cats received placebo or one dose of ivabradine at 0.1 mg/kg, 0.3 mg/kg, or 0.5 mg/kg, PO. HR and blood pressure were monitored continuously for 24 hours via radiotelemetry after each treatment. Response to stress was studied twice by 15-min acoustic startle applied at baseline and 4 hours after drug. Statistical comparisons were made using a linear mixed model and 2-way repeated measures ANOVA. Peak negative chronotropic effect was observed 3 hours after ivabradine administration. Heart rate (min-1) decreased significantly (p<0.05) in a dose-dependent manner (mean±SD for placebo: 144±20; ivabradine 0.1 mg/kg: 133±22; ivabradine 0.3 mg/kg: 112±20; ivabradine 0.5 mg/kg, 104±11). Heart rate (min-1) was still reduced (p<0.05) at 12 hours after ivabradine (0.3 mg/kg: 128±18 and 0.5 mg/kg: 124±16) compared to placebo (141±21). Heart rate response to acoustic startle was significantly (p<0.01) blunted at all 3 doses of ivabradine. No effect of ivabradine on blood pressure was identified and no clinically discernable side effects were observed. These findings indicate that ivabradine at 0.3 mg/kg and 0.5 mg/kg PO predictably lowers HR for at least 12 hours in healthy cats. Clinical studies in cats with HCM are needed. Advisors/Committee Members: Schober, Karsten (Advisor).

Subjects/Keywords: Animals; Veterinary Services; Ivabradine; Heart Rate; Pharmacodynamics; If inhibitor

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APA (6^th Edition):

Cober, R. E. (2010). Effects of Ivabradine, A New Selective If Current Inhibitor, on Heart Rate in Cats. (Masters Thesis). The Ohio State University. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=osu1272998433

Chicago Manual of Style (16^th Edition):

Cober, Richard E. “Effects of Ivabradine, A New Selective If Current Inhibitor, on Heart Rate in Cats.” 2010. Masters Thesis, The Ohio State University. Accessed October 19, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1272998433.

MLA Handbook (7^th Edition):

Cober, Richard E. “Effects of Ivabradine, A New Selective If Current Inhibitor, on Heart Rate in Cats.” 2010. Web. 19 Oct 2019.

Vancouver:

Cober RE. Effects of Ivabradine, A New Selective If Current Inhibitor, on Heart Rate in Cats. [Internet] [Masters thesis]. The Ohio State University; 2010. [cited 2019 Oct 19]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1272998433.

Council of Science Editors:

Cober RE. Effects of Ivabradine, A New Selective If Current Inhibitor, on Heart Rate in Cats. [Masters Thesis]. The Ohio State University; 2010. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1272998433

University of Cincinnati

28. Samineni, Divya. Pre-Clinical and Clinical Investigation of Pharmacokinetic and Pharmacodynamic Interactions between Darunavir, a Novel Protease Inhibitor and Rosuvastatin.

Degree: PhD, Pharmacy: Pharmaceutical Sciences/Biopharmaceutics, 2011, University of Cincinnati

URL: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1314040722

► Treatment of dyslipidemia in HIV-infected persons is commonly required with the use of protease inhibitors (PIs) which may be restricted by drug-drug interactions between… (more)

▼ Treatment of dyslipidemia in HIV-infected persons is commonly required with the use of protease inhibitors (PIs) which may be restricted by drug-drug interactions between antiretroviral agents and statins. We hypothesized that darunavir/ritonavir (DRV/rtv) modulate the pharmacokinetics of rosuvastatin (RSV) when co-administered by altering its hepatic disposition. The plausible genetic influence on the plasma exposure of RSV was also explored. To investigate this hypothesis, we first conducted a clinical drug interaction study and subsequently performed in vitro correlative/mechanistic analysis. In the open label, crossover study, 12 healthy volunteers were randomized to receive either RSV 10 mg/day or DRV/rtv 600/100 mg (bid) and in combination for 7 days followed by a crossover to the other regimen for 7 more days. The fasting lipids were obtained at baseline and on days 7, 21 and 35 along with intensive PK sampling for 24 hours post-dose. The PK parameters such as Cmax, t1/2 and AUC0-24 were determined by non-compartmental analysis using WinNonLin 5.2. Statistical analyses were performed using Paired t test. Drug levels were compared with OATP1B1 c.521T > C, 388A>G, BCRP c.421 C > A, MRP2 c. -24C>T, 1249G>A, 3972C>T single nucleotide polymorphisms (SNPs) to investigate potential outliers in the drug interaction study. Next we assessed the influence of DRV on the activity of multidrug transporters OATP1B1, BCRP and Pgp in the transporter over-expressing CHO and MDCK cells and primary human hepatocyte cultures. The AUC0-24 and Cmax of RSV before and after administration of DRV/rtv showed a significant increase by 1.48 fold ( P=0.003) and 2.44 fold (P<0.001) without a change in the t1/2 (P=0.176). However the AUC, Cmax, and t1/2 of DRV and RTV were unaltered. The total cholesterol increased by a median 4% (P=0.002) when RSV was given in combination than when given alone. Furthermore, we observed a trend toward lower plasma exposure of RSV in subjects with OATP1B1 *1a/*15 than OATP1B1*1a/*1a genotypes. And no adverse events were attributable to the drug interaction. Our in vitro findings suggest that DRV/rtv led to an inhibition of OATP1B1 (IC50 = 10 µM) and BCRP (IC50 = 77 µM) and an induction in Pgp activity (p= 0.05) Co-administration of DRV/rtv significantly increased the plasma exposure of RSV and consequently led to a decline in the lipid-lowering effects of RSV. This study warrants large-scale interaction in HIV-infected population. Advisors/Committee Members: Desai, Pankaj (Committee Chair).

Subjects/Keywords: Pharmaceuticals; Pharmacokinetics; Pharmacodynamics; Pharmacogenomics; Rosuvastatin; Darunavir; OATP1B1 Uptake

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APA (6^th Edition):

Samineni, D. (2011). Pre-Clinical and Clinical Investigation of Pharmacokinetic and Pharmacodynamic Interactions between Darunavir, a Novel Protease Inhibitor and Rosuvastatin. (Doctoral Dissertation). University of Cincinnati. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=ucin1314040722

Chicago Manual of Style (16^th Edition):

Samineni, Divya. “Pre-Clinical and Clinical Investigation of Pharmacokinetic and Pharmacodynamic Interactions between Darunavir, a Novel Protease Inhibitor and Rosuvastatin.” 2011. Doctoral Dissertation, University of Cincinnati. Accessed October 19, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1314040722.

MLA Handbook (7^th Edition):

Samineni, Divya. “Pre-Clinical and Clinical Investigation of Pharmacokinetic and Pharmacodynamic Interactions between Darunavir, a Novel Protease Inhibitor and Rosuvastatin.” 2011. Web. 19 Oct 2019.

Vancouver:

Samineni D. Pre-Clinical and Clinical Investigation of Pharmacokinetic and Pharmacodynamic Interactions between Darunavir, a Novel Protease Inhibitor and Rosuvastatin. [Internet] [Doctoral dissertation]. University of Cincinnati; 2011. [cited 2019 Oct 19]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1314040722.

Council of Science Editors:

Samineni D. Pre-Clinical and Clinical Investigation of Pharmacokinetic and Pharmacodynamic Interactions between Darunavir, a Novel Protease Inhibitor and Rosuvastatin. [Doctoral Dissertation]. University of Cincinnati; 2011. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1314040722

Universiteit Utrecht

29. 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 October 19, 2019. 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. 19 Oct 2019.

Vancouver:

Zandvliet AS. Population pharmacokinetic and pharmacodynamic modeling and simulation of the investigational anticancer agent indisulam. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2007. [cited 2019 Oct 19]. 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

30. 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 October 19, 2019. 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. 19 Oct 2019.

Vancouver:

Klümpen HJ. Personalized medicine of targeted anti-cancer drugs. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2012. [cited 2019 Oct 19]. 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

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