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1
Chigutsa, Emmanuel. "Population pharmacokinetics and pharmacokinetic-pharmacodyamic modeling of antitubercular drugs". Doctoral thesis, University of Cape Town, 2013. http://hdl.handle.net/11427/3275.
Testo completoAbstract (sommario):
Includes abstract.Includes bibliographical references.
The pharmacokinetics of rifampicin, isoniazid, pyrazinamide and ethambutol in 78 patients with tuberculosis were described using non-linear mixed effects modeling. Pharmacodynamic data was comprised of weekly sputum liquid culture (using mycobacterial growth indicator tubes) time to detection results from 144 patients during the first 2 months of treatment. The effect of drug exposure on patient outcomes was investigated. To determine the adequacy of ofloxacin drug exposure, the probability of attaining the required area-under-the-curve to minimum inhibitory concentration ratio (AUC/MIC) of ofloxacin was determined in 65 patients on treatment for multidrug resistant tuberculosis. To improve efficiency in the clinical development of new drug regimens, clinical trial simulation was used to determine the optimal study design for a study investigating the efficacy of a new antitubercular drug regimen. The SLCO1B1 rs4149032 polymorphism existed at a high frequency of 0.70 in South Africans and resulted in a 28% decrease in bioavailability of rifampicin. The rifampicin peak concentration was a significant predictor of the 2 month treatment outcomes. A semimechanistic time to event model was developed to analyze days to positivity (time to detection) data. The model was comprised of a biexponential decay model describing bacillary decline in sputum from patients, followed by a logistic model with a lag time for growth of the mycobacteria in liquid culture. For the current 800 mg daily dose of ofloxacin, the probability of attaining an AUC/MIC target ratio of at least 100 was only 0.45. Based on clinical trial simulation, the optimum parallel study design was comprised of 125 study participants in each of 2 arms to achieve a study power of at least 80%. Increasing the study length beyond 42 days reduced study power perhaps due to increased amounts of censored data. Higher doses of rifampicin are required in the majority of South African patients with tuberculosis. A novel pharmacodynamic model of tuberculosis treatment is presented, which can be used for investigation of covariates such as drug exposure. Ofloxacin should be replaced with a more potent fluoroquinolone for treatment of multidrug resistant tuberculosis. Clinical trials should not be unduly long otherwise this may compromise study power.
2
Ulrich-Oppliger, Brigitte Madeleine. "Pharmacokinetics /". Bern, 1992. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
Testo completo
3
Charter, Mark Keith. "Maximum entropy pharmacokinetics". Thesis, University of Cambridge, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.316691.
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4
Smith, Jennifer Lisa. "Pharmacokinetics of methylamines". Thesis, Massachusetts Institute of Technology, 1992. http://hdl.handle.net/1721.1/12906.
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5
Khosravan, Reza. "Nonlinear pharmacokinetics of diltiazem". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape9/PQDD_0030/NQ46865.pdf.
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6
Al-Mustafa, Z. H. "Methotrexate pharmacokinetics and toxicity". Thesis, University of Newcastle Upon Tyne, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.383988.
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7
Woodhouse, Jennifer Ann. "Plutonium pharmacokinetics and blood biochemistry". Thesis, University of Central Lancashire, 1997. http://clok.uclan.ac.uk/20148/.
Testo completoAbstract (sommario):
Since its discovery in the early 1940s the element plutonium has been seen by mankind as both an opportunity and a threat. As a radioactive nuclide plutonium presents health hazards in its handling and if mankind is to make the most of this element's potential benefits it is essential that these hazards be understood. Both overestimation and underestimation of these hazards are damaging to its proper utilisation. Many studies have been carried out to determine the effects of plutonium exposure and a broad picture of the biological behaviour of plutonium has been built up. Radiological protection standards are based on such broad understanding and a "Central Dogma" has arisen viz, plutonium is bound avidly in liver and bone; clearance half-lives from these organs differ (by a factor of 2.5) but are very long - a minimum of 50 years for bone; this is why plutonium urinary excretion levels are very low. Despite all the research work that has been carried out there are many important areas of plutonium behaviour which are not well understood or in which the central ideas adopted for radiological protection purposes are questionable. One such questionable area is extended half-life in the body. Two rather different areas relate to the molecular binding interactions which plutonium enters into in body tissues and transfer mechanisms from blood into cellular organelles. Very little is known about these processes and the speciation that plutonium demonstrates within the body. This thesis explores understanding of plutonium behaviour by application of pharmacokinetic theory to observed human behaviour, both following occupational exposure and experimental injection. Occupational exposure data demonstrated behaviour consistent with pharmacokinetic expectations over periods of 25 years or more. Long-term half-lives were 10 to 30 years rather than 50 to 100 years or more. There was no evidence of differing half-lives between liver and bone. Very low renal clearance was seen in intravenous injection studies suggesting either very extensive plutonium binding to the protein transferrin in blood or pointing to reabsorption in the kidney tubule after glomerular filtration. This latter possibility might lead to a "Plutonium blood pressure" which effectively forces activity into tissues irrespective of the strength of binding forces. Experimental work indicated species differences in transferrin binding which may have relevance for extrapolation from animals to humans.
8
Smith, Adam John. "Modulating the Pharmacokinetics of Bioflavonoids". Scholar Commons, 2012. http://scholarcommons.usf.edu/etd/4226.
Testo completoAbstract (sommario):
One of the largest obstacles in drug development is to overcome solubility and bioavailability problems. Preformulation strategies such as nanoparticle formation are often employed but sometimes create new issues and are limited in their effectiveness and applications. Since the majority of drugs are marketed and sold as solid forms, drug delivery systems are not always desirable. This is where solid-state chemistry becomes important. Traditional solid-state chemistry approaches are often successful but are sometimes too restrictive and cannot be applied to certain compounds. Cocrystals have emerged as an alternative solid-state technique that can be applied to a broad range of compounds. However, the technology is still very new and its effectiveness in certain conditions had previously not been evaluated.
The studies detailed herein investigated the ability of two different technology platforms for overcoming drug design challenges for two promising bioflavonoids: EGCg and quercetin. Studies have shown that EGCg might be useful for the treatment of Alzheimer's disease and other neurodegenerative diseases. Quercetin is being investigated for numerous bioactivities and is currently being marketed as an energy dietary supplement. Both of these bioflavonoids exhibit poor bioavailability and water solubilities that are at opposite ends of the spectrum. In the chapters to follow, nanoparticle technology was applied to EGCg and evaluated in cell models of AΒ production, a hallmark of Alzheimer's disease. Bioavailability improvements were also evaluated in rats. Additionally, new forms of both flavonoids were created using cocrystallization. These new cocrystals were characterized using powder and single crystal x-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis. Solubility and bioavailability changes were also evaluated. These data have strong implications in drug development since they elucidated the strengths and weaknesses of two major technologies in compounds with different design challenges.
9
Harper, Kenneth W. "Pharmacokinetics of methohexitone and midazolam". Thesis, Queen's University Belfast, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.254195.
Testo completo
10
Evans, Gary Lee. "Pharmacokinetics and metabolism of lacidipine". Thesis, University of Hertfordshire, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.387196.
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11
Ahsan, Chowdhury Hafizul. "Pharmacokinetics of nifedipine in humans". Thesis, University of Southampton, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.303154.
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12
Richards, Robert. "The pharmacokinetics of sodium cromoglycate". Thesis, University of Southampton, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.359034.
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13
Bester, Lynette. "Pharmacokinetics of propofol in cats". Diss., University of Pretoria, 2009. http://hdl.handle.net/2263/22954.
Testo completoAbstract (sommario):
Since the introduction of the lipid emulsion formulation in 1986, propofol has become established for induction as well as for maintenance of anaesthesia in veterinary practice1 including cats2;3-8. Propofol is rapidly metabolized by hepatic glucuronidation in most species and it has also been shown to undergo extrahepatic metabolism9-13, so that total body clearance may exceed liver blood flow in certain species. Because of their highly carniverous diet, cats are little exposed to antiherbivory compounds so that they have become deficient in UGP-glucuronosyltransferase (UGT)14. Consequently, a number of drugs are eliminated slowly15;16, often giving rise to prolonged half-lives of the parent drugs. Cats are therefore sensitive to the adverse effects of many drugs and toxins that are normally glucuronidated before elimination. It is therefore likely that the disposition of propofol may differ markedly from that of humans and other animal species17. Adam et al18 reported that for the cremophor propofol formulation in cats, volumes of distribution were smaller and elimination halflives were longer than those of pigs, rats and rabbits. In addition, pulmonary uptake has been demonstrated to occur in cats,19 however propofol’s pharmacokinetics have not been studied formally. The purpose of this study was to determine the pharmacokinetic behaviour of propofol after single intravenous injections. In comparison with man, the apparent central volume of distribution in domestic cats is small (0.56L.kg-1 body weight vs. 0.228L.kg-1) for the human pharmacokinetic parameter set of Marsh et al20 and the clearance (0.0086 L.kg-1.min-1 vs. 0.027 L.kg- 1.min-1) is approximately 2½ times slower in cats when compared with humans. Slow clearance should not influence recovery from anaesthesia following standard induction doses, because the early decreases in blood concentrations are predominantly due to redistribution of drug to various tissues (similar to the disposition of thiopentone which exhibits a slow total body clearance21. However it is possible that drug may accumulate within the body after prolonged infusions, resulting in delayed recovery times. This phenomenon is best described by calculating “context-sensitive” decrement-times by computer simulation22-24. Computer software♣ were used to calculate the 20%, 50% and 80% context-sensitive decrement times for the cat pharmacokinetic model. For comparative purposes, similar calculations were performed for an adult human male (weight 70 kg) using the pharmacokinetic parameter-set of Marsh et al20. Assuming that recovery from anaesthesia occurs after a 50% decrease in blood concentrations has taken place, it is apparent from the 50% context-senstive decrement-time graph that for infusions lasting up to 20 minutes (during which concentrations are kept constant), recovery can be expected to be rapid and predictable. However if infusions are administered for longer than 20 minutes, the recovery times of the “average” cat increase rapidly, reaching a plateau of 36 minutes, while recovery times of the human remain short, albeit increasing slowly. Awakening times become dramatically prolonged and unpredictable in both cats and humans if propofol concentrations are required to decrease by 80% for recovery to occur. Under these circumstances the 80% decrement time after a two-hour infusion is approximately two hours in cats and 45 minutes in humans. On the other hand, if dosing is conservative, so that blood concentrations need to decrease by only 20% for awakening to occur, then recovery times are short and predictable, being only a few minutes, regardless of the duration of the preceding infusion. These findings are in accordance with those of Pascoe et al25 who reported that cats took longer to recover after a short (30 min) infusion than after a long (150 min) infusion. In their crossover study, the propofol infusion rates were adjusted so that the cats were maintained at a light level of anaesthesia at which they responded sluggishly to pedal stimulation. It is therefore likely that propofol concentrations were kept steady and were similar during the 30-minute as well as during the 150-minute infusions. Delayed recovery has also been reported when propofol was administered to cats on consecutive days26. Conclusions and clinical relevance: We recommend that propofol infusions be administered to cats only for fairly short procedures and that for prolonged surgery, maintenance of anaesthesia should be accomplished using other drugs. In order to decrease the propofol dose, premedication and analgesic supplements should be co-administered to provide “balanced” anaesthesia. ♣ TIVA Trainer version 8, author Frank Engbers, Leiden University Medical Centre CopyrightDissertation (MMedVet)--University of Pretoria, 2009.
Companion Animal Clinical Studies
unrestricted
14
Tongaree, Sauwaluxana. "Vancomycin pharmacokinetics : development and assessment". Scholarly Commons, 1991. https://scholarlycommons.pacific.edu/uop_etds/2224.
Testo completoAbstract (sommario):
An evaluation of vancomycin pharmacokinetics was performed in 2 phases. In phase I, a vancomycin population pharmacokinetic model was developed based on data from 126 patients using a two-compartment model. Variables tested for inclusion in the model were creatinine clearance (Crcl), age, total body weight (wt) ICU status, gender, body surface area, ideal weight and height. Variables were included at the P < _ 0. 05 level. The final population pharmacokinetic model was as follows: Cl (L/hr) = (0.025 * Crcl) * (1 + 0.0165 *age), V1 (L) = 29.5, V2 (L) = 8.17 + 0.349 * Crcl and Q (L/hr.kg) = 0. 0639 * wt. For ICU patients, V2 was larger than the non ICU patients and it was V2 (L) = 16.258 + 0.694 * Crcl.
In phase II, the performance of the derived model was evaluated and compared to the Moellering, Matzke, Birt & Chandler and Rodvold Methods. Predictability of .52 vancomycin serum concentrations was assessed in 3 0 new patients. In predicting all concentration types, mean prediction error (MPE) with 95% CI for Moellering,. Matzke, Birt & Chandler, Rodvold and current methods were -0.1 (-1.6, 1.4), -0.8 (-0.7, 2. 4) , o. o ( -1.5, 1. 6) , -2. 0 ( -3. 4, -o. 5) , and 2. 1 ( o. 9, 3. 4) mg/L respectively. When considering only troughs, MPE with 95% CI were 1.8 (0.2, 3.4), 2.7 (0.9, 4.6), -1.5 (-3.5, 0.5), -1.5 (-3.2, 0.1), and 0.8 (-0.8, 2.4) mg/L respectively. MPE with 95% for the peaks were -2.5 (-5.0, 0.0), -1.6 (-4.1, 1.0), 2.0 (-0.4, 4.4), -2.5 (-5.3, 0.3) and 3.8 (1.8, 5.8) mg/L respectively.
Median absolute prediction error (MABPE) , 5% and 95% quantiles for all concentration types for Moellering, Matzke, Birt & Chandler, Rodvold and current methods were 3.4 (0.2, 10.1), 4.1 (0.3, 10.9), 3.9 (0.4, 11.7), 3.1 (0.2, 13.0) and 2.3 (0.1, 9.5) mg/L respectively. MABPE, 5% and 95% quantiles for the troughs were 2. 6 ( o. 2, 9. 4) , 4. o ( o. 4, 10. 3) , 4. 1 (0.7, 10.2), 2.9 (0.2, 9.4) and 2.0 (0.1, 9.2) mg/L respectively. MABPE, 5% and 95% quantiles for the peaks were 5.0 (0.7, 11.5·), 4.2 (0.3, 10.9), 3.8 (0.4, 11.7), 4.9 (0.6, 13.0) and 5.0 (1.1, 9.5) mg/L respectively.
It is recommended that the current method be used while setting initial target peak at 30 mg/L with the initial target trough at 6 mgjL. This should frequently result in serum vancomycin concentration within the therapeutic window. Individualization of therapy should then be done when the measured concentrations are available.
15
Bester, Lynette. "Pharmacokinetics of propofol in cats". Pretoria : [s.n.], 2021. http://upetd.up.ac.za/thesis/available/etd-03032010-184513/.
Testo completo
16
Dragula, Collen Elizabeth 1964. "A pharmacokinetic study of acrylamide and theophylline in rats". Thesis, The University of Arizona, 1988. http://hdl.handle.net/10150/276847.
Testo completoAbstract (sommario):
Effects of age, dosage regimen, dose level, and routes of administration on the pharmacokinetics of acrylamide (ACR) and theophylline (TP) in Fischer 344 rats have been studied. ACR treatment consisted of administration of a single subtoxic dose or of multiple doses known to induce neurotoxicity to 5 and 11 week old rats. The effects of age and dosing regimen on the determination of pharmacokinetic parameters were studied. Multiply dosed rats had significantly longer plasma half lives than the singly dosed animals. Clearance values in the plasma were also significantly decreased following multiple dosing. Animals treated with TP received a single dose at different dose levels either intravenously or orally. No statistical difference was found between beta, Vbeta , and Cl based on dose level. All pharmacokinetic parameters were similar in magnitude to literature values for humans. Following oral dosing, plasma levels of TP were constant for the duration of the experiment. (Abstract shortened with permission of author.)
17
Olsén, Lena. "Drugs in horses : pharmacokinetics and pharmacodynamics /". Uppsala : Dept. of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, 2007. http://epsilon.slu.se/200737.pdf.
Testo completo
18
Tärning, Joel. "Piperaquine : bioanalysis, drug metabolism and pharmacokinetics /". Göteborg: Institute of Neuroscience and Physiology, Dept. of Pharmacology, the Sahlgrenska Academy at Göteborg University, 2007. http://hdl.handle.net/2077/7196.
Testo completo
19
Siccardi, Marco. "Genetic determinants of key antiretroviral pharmacokinetics". Thesis, University of Liverpool, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.569560.
Testo completoAbstract (sommario):
Antiretroviral pharmacokinetics is one of the most important predictors of therapy efficacy and correlations between virological suppression and plasma concentrations have been described for all antiretroviral classes. Plasma concentrations are the result of absorption, distribution, metabolism and elimination (AD ME) processes which are mediated by numerous proteins in different tissues. Single nucleotide polymorphisms (SNPs) in genes encoding for individual proteins may be an important determinants drug exposure. The aim of this thesis was to characterise the role of some key SNPs determining antiretroviral plasma concentrations in order to improve the current understanding of dose-dependent efficacy and toxicity. A number of different strategies to investigate the role of genetic variability in antiretroviral exposure were developed in this thesis. The polymorphism 63396 C>T in the PXR gene, a nuclear factor regulating the expression of CYPs and transporter in hepatocytes, was proven to influence unboosted atazanavir clearance using a pharmacogenetic based population phannacokinetic model and patients with 63396TT genotype had a increment in ATV clearance of 17% (Chapter 2). In Chapter 3, the predictors of intracellular phannacokinetic of unboosted and boosted atazanavir were investigated and expression of SLC03Al, an uptake transporter expressed on PBMC was correlated with cellular accumulation of boosted and unboosted atazanavir (rho=0.706, p=0.010; rho = 0.830, P = 0.005, respectively). An in vitro in vivo extrapolation model for efavirenz was developed in Chapter 4 and the effect of CYP2B6 516 G>T on standard regimens or dose reduction was quantified. Efavirenz pharmacokinetics was predicted with good accuracy compared to available data; simulated Ctrough was 2119 ng/ml vs 1764 ng/ml, simulated Cmax was 3725 ng/ml vs 4063 ng/ml. The effect of 516G>T on simulated EFV clearance (GT = - 24% and TT = -58%) was comparable to previously published population phannacokinetic data (GT =-36%, TT =-66%). Maraviroc, a CCR5 inhibitor was identified as a substrate for SLC01B1 with a Km of 33.85 IlM and Vmax of 187.9 finol/oocyte/min and the inhibitory potential of concomitant protease inhibitors on this transporter was investigated using Xenopus laevis oocytes heterologous protein expression system (Chapter 5). Moreover the SNP SLCOIBl 521 T>C was correlated with maraviroc Ctrough in a cohort of HIV infected patients; MVC Ctrough in SLC01B1 521 heterozygote patients (TC) (n=8) was higher than in wild type homozygotes (TT) (n=22), 103 ng/ml (69 - 124) vs 46 ng/ml (28 - 66), p=0.003 (Chapter 6). The convergence of different factors under study permitted partial definition of the complex interplay in which drug-drug interactions and physical characteristics interact with genetic variability to define the phannacokinetic phenotype. These findings will help identify patients with a higher risk of achieving sub-therapeutic or potentially toxic plasma concentrations and will serve as a knowledge-base from which to grow and validate strategies for optimisation of therapy.
20
Khazal, Kamel F. "Chloramphenicol pharmacokinetics and metabolism in dogs /". The Ohio State University, 1986. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487267024996335.
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21
Song, Di. "Bladder tissue pharmacokinetics of anticancer drugs /". The Ohio State University, 1996. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487940308433249.
Testo completo
22
Arends, Rosalinda Helena Gerardus Petronella. "Pharmacokinetics and pharmacodynamics of opioid analgesics /". Thesis, Connect to this title online; UW restricted, 1998. http://hdl.handle.net/1773/7955.
Testo completo
23
Wright, Abra M. "Pharmacokinetics of pergolide in normal mares". Thesis, Manhattan, Kan. : Kansas State University, 2009. http://hdl.handle.net/2097/1548.
Testo completo
24
Eriksson, Tommy. "Pharmacokinetics of the enantionmers of thalidomide". Malmö : Lund : Malmö University Hospital ; Lund University, 1997. http://catalog.hathitrust.org/api/volumes/oclc/68945032.html.
Testo completo
25
Walker, Roderick Bryan. "HPLC analysis and pharmacokinetics of cyclizine". Thesis, Rhodes University, 1995. http://hdl.handle.net/10962/d1003279.
Testo completoAbstract (sommario):
The investigations detailed in this dissertation have been conducted to address the paucity of pharmacokinetic information, in published literature, pertaining to cyclizine. The areas of investigation have included the selective quantitation of both cyclizine and its demethylated metabolite, norcyclizine in serum and urine, assessment of stability of both compounds in stored biological samples, dosage form analysis, dissolution rate testing of tablets, and bioavailability and pharmacokinetics following administration of an intravenous solution, and tablets to humans. High-performance liquid chromatography (HPLC) was used as the main analytical technique throughout these studies. An original HPLC method employing ultraviolet detection with a limit of quantitation of 5μg/ℓ was developed for the determination of cyclizine in serum and both cyclizine and norcyclizine in urine, Solid-phase extraction using extraction columns packed with reversed-phase C18 material, and followed by a simple phase-separation step proved successful for the accurate and precise isolation of the compounds. The validated method was applied to the analysis of serum and urine samples from a pilot study in which a single volunteer was administered 50mg of cyclizine hydrochloride. Several samples collected during the pilot study revealed the presence of both drug and metabolite in concentrations below the limit of detection. In order to improve the selectivity and sensitivity of the analytical method an HPLC method with electrochemical detection operating in the "oxidative-screen" mode was developed. The solid-phase extraction procedure was modified slightly and the method found to be precise, accurate, selective and highly sensitive with a limit of quantitation of Iμg/g/l for both cyclizine and norcyclizine in both serum and urine. This method was applied to the determination of both compounds after intravenous and oral administration of cyclizine to humans. HPLC with electrochemical detection was used for the analysis of samples collected during dissolution studies on the batch of tablets used for pharmacokinetic studies. In addition, this method was used to assess content uniformity of the tablets and of samples from the batch of intravenous ampoules of cyclizine lactate. Dissolution studies showed that all tablets tested passed the compendial specifications for cyclizine. Content uniformity assessment revealed that within-batch uniformity existed for both the tablets and ampoules and, therefore, variations in pharmacokinetic parameters for the drug would more than likely be as a result of inter- and intra-individual variability within the subject population. Pharmacokinetic information for cyclizine was obtained following administration of an intravenous bolus dose of cyclizine lactate as a solution, oral administration of cyclizine hydrochloride as a single dose of 50mg and as fixed multiple doses of 50mg every 8 hours for five days. Further information was acquired following administration of single doses of 100mg and 150mg cyclizine hydrochloride. Data collected from these studies were evaluated using both compartmental and non-compartmental techniques. Cyclizine was rapidly absorbed following oral administration with mean kₐ = 1.54 hr⁻¹ and was found to have an absolute bioavailability (F) of 0.47. The presence of norcyclizine in serum following oral and not intravenous dosing suggests cyclizine is susceptible to "first-pass" metabolism in either the gut wall or the I iver. Mean ClTOT determined following the intravenous dose was 0.865 ℓ/hr/kg. The mean ClTOT of 0.823 ℓ/hr/kg calculated following oral dosing, using a unique value of F for each subject compared favourahly with that obtained following intravenous dosing. Renal clearance of cyclizine is negligihle indicating that non-renal routes of elimination account for the majority of removal of cyclizine form the body. Cyclizine is extensively distributed and the mean Vz following an intravenous dose was 16.70 ℓ/kg. This value is lower than that calculated from all oral studies from which the mean Vz was determined to be 25.74 ℓ/kg. Cyclizine is eliminated slowly with a mean elimination t½ = 20.11 hours. Cyclizine dose not appear to follow dosedependent kinetics and therefore, inability to predict steady state levels are more than likely due to accumulation as a result of frequent dosing rather than saturation of elimination mechanisms. Modelling of intravenous data to one-compartment (lBCM), two-compartment (2BCM) and threecompartment models indicated that the pharmacokinetics of cyclizine can be adequately described by a 3BCM. The drug is rapidly distributed into a "shallow" peripheral compartment (α = 9.44 hr⁻¹ , and k₂₁ = 2.09 hr⁻¹ ), and slowly distributed to the "deep" peripheral compartment (β = 0.451 hr⁻¹ and k₃₁ = 0.120 hr⁻¹ ). Modelling of all oral data indicated that a 2BCM best described the pharmacokinetics of the drug, however, distribution to the peripheral compartment is not as rapid as to the "shallow" peripheral compartment following the intravenous dose. Mean distribution parameters were α = 0.64 hr⁻¹1 and, k₂₁ = 0.39 hr⁻¹. Mean CITOT following intravenous dosing of 0.70 ℓ/hr/kg was similar to the mean CIToT of 0.73 ℓ/hr/kg determined after oral dosing. The mean distribution volume at steady state determined following intravenous dosing (17.78 ℓ/kg) was lower than that obtained from the oral studies (25.52 ℓ/kg). The mean terminal elimination half-lives calculated for cyclizine following fitting of intravenous and oral data was 25.09 hours. In general, mean pharmacokinetic parameters calculated following titting of data to a 2BCM after oral administration correlate closely with those calculated using non-compartmental techniques. However, the pharmacokinetics following intravenous dosing are better described by a 3BCM and a close correlation between parameters estimated using noncompartmental techniques and compartmental techniques is evident when a 3BCM model is used.
26
Rigby, Justin Holbrook. "Pharmacokinetics of Dexamethasone Delivered via Iontophoresis". BYU ScholarsArchive, 2013. https://scholarsarchive.byu.edu/etd/3895.
Testo completoAbstract (sommario):
Study Design: Controlled laboratory study. Objectives: To determine the time course of dexamethasone sodium phosphate (Dex-P) iontophoresis delivery to underlying tissues using microdialysis. Background: The efficacy of iontophoresis at delivering Dex-P through the skin is unknown in humans because of the lack of minimally invasive measurement techniques. Methods: Sixty-four healthy male participants (age = 24.4 ± 3.3 yrs, height = 71.8 ± 2.5 in, weight = 181.8 ± 26.1 lbs) were randomly assigned into one of six groups: 1) 1 mA current, 1 mm probes depth ; 2) 1 mA current, 4 mm probes depth; 3) 2 mA current, 1 mm probes depth; 4) 2 mA current, 4 mm probes depth; 5) in vivo retrodialysis; and 6) skin perfusion flowmetry. Microdialysis probes assess the combined recovery (Dextotal) of Dex-P, dexamethasone (Dex) and its metabolite. In vivo calibration of the microdialysis probes occurred via retrodialysis. Laser Doppler flowmetry assessed skin perfusion. Results: There was no difference of Dextotal between current intensities (P = 0.99) but a greater amount of Dextotal was recovered by the 1 mm probe (P < 0.0001) compared to the 4 mm probe. Peak means for the 1 and 2 mA at 1 mm were 10.8 ± 8.1 and 7.7 ± 5.5 μg/ml and at 4mm being 2.0 ± 0.8 and 1.3 ± 0.9 μg/ml, respectively. Skin perfusion rapidly increased during both current intensity treatments, but significantly decreased before the conclusion of the 1 mA treatment (P < 0.0001). Peak skin perfusion was 741.4 ± 408.7% and 711.6 ± 260.8% baseline for 1 and 2 mA intensities, respectively. Conclusion: Iontophoresis delivery of Dex-P was successful measured in vivo through human skin. Significant concentrations of Dextotal were found regardless of current intensity. Though current induced vasodilation occurred, it did not significantly affect the tissue accumulation of Dextotal.
27
Methaneethorn, Janthima. "Population pharmacokinetics and pharmacodynamics of pyronaridine". Diss., University of Iowa, 2013. https://ir.uiowa.edu/etd/4876.
Testo completoAbstract (sommario):
Pyronaridine/Artesunate (PA) 3:1 fixed dose combination is a novel artemisinin-based combination therapy (ACT) in development for the treatment of acute uncomplicated Plasmodium falciparum or Plasmodium vivax malaria. An understanding of both pharmacokinetics and pharmacodynamics of pyronaridine is of importance in order to achieve optimal therapeutic outcome.
In this thesis, population pharmacokinetic models for pyronaridine in healthy subjects, and adult and pediatric malaria patients were developed. Pyronaridine pharmacokinetics in both adult and pediatric populations were best described by a two compartment model with first order absorption and elimination from the central compartment. A presence of malaria infection and body weight were the significant covariates that explained pyronaridine pharmacokinetic variability in the adult population. For the pediatric population, age was the only significant covariate that explained pyronaridine pharmacokinetic variability.
Monte Carlo simulations were also performed to address differences in pyronaridine exposures among these populations and to explore the exposures of pyronaridine among recommended dosage regimens for pediatric and adult malaria patients. Healthy adults had a higher exposure to pyronaridine as compared to adult malaria patients. For the pediatric population, younger children had a higher exposure to pyronaridine as compared to older children. The overall range of pyronaridine exposures among dosing groups for adult and pediatric malaria patients were relatively similar.
The cut-off values of pyronaridine pharmacokinetic parameters associated with successful treatment outcome were also determined by means of receiver operating characteristic (ROC) curve. These cut-off values can be used to optimize the outcome of malaria treatment. Additionally, Cox proportional hazard model was conducted to determine the relationship between several covariates and time to the occurrence of re-infection or recrudescence. The models showed that as the levels of predicted pyronaridine concentrations on day 7 increased, the risks of acquiring re-infection or recrudescence decreased.
Finally, pharmacokinetic drug-drug interaction of pyronaridine and ritonavir was assessed based on the overlap pathway for metabolism of both drugs and the high rates of HIV and malaria co-infection. There was an effect of ritonavir on pyronaridine pharmacokinetics. However, the results were not considered clinically relevant. An increase in ritonavir exposure was observed in the presence of fixed dose PA.
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Pigatto, Maiara Cássia. "Modelagem PK/PD do efeito anticancerígeno do etoposídeo em ratos com tumor de walker-256 utilizando concentrações livres intratumorais determinaas por microdiálise". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2015. http://hdl.handle.net/10183/148189.
Testo completoAbstract (sommario):
Objetivo: O objetivo do presente estudo foi descrever a relação entre as concentrações plasmáticas totais e livres tumorais do etoposídeo (ETO) e a inibição do crescimento do tumor observada em ratos Wistar portadores de tumor Walker- 256 (W256) utilizando a modelagem farmacocinética/farmacodinâmica (PK/PD). Métodos: Os procedimentos com animais foram aprovados no CEUA/UFRGS sob o número 22302. Os experimentos de farmacocinética foram realizados para determinar concentrações plasmáticas e livres em duas regiões do tumor sólido W256 através de microdiálise. Após a administração do ETO nas doses de 10 ou 20 mg/kg i.v. bolus em ratos Wistar portadores de tumor W256, amostras de sangue e microdialisado de tecido do centro e periferia do tumor foram coletadas simultaneamente, até 7 h pós-dose, para determinar o fator de penetração no tumor. Um método analítico por CLAE-UV foi desenvolvido e validado para quantificação do etoposídeo nas amostras de plasma e dialisado. Os experimentos de farmacodinâmica foram conduzidos em ratos portadores de tumor W256 que receberam ETO 5 e 10 mg/kg i.v. bolus uma vez ao dia por 8 e 4 dias, respectivamente. O volume dos tumores foram monitorados diariamente durante 30 dias. Análise não-compartimental dos dados de PK foi realizada no WinNonlin®. A modelagem dos dados PK e PK/PD foi realizada no Monolix®, utilizando abordagem populacional. Os dados PK/PD foram analisados usando o modelo Simeoni TGI modificado através da introdução de uma função Emax para descrever a relação nãolinear entre a concentração plasmática e tumoral e o efeito. Resultados e Discussão: O método por CLAE-UV foi desenvolvido e validado para quantificar as amostras de ETO em plasma e tecido. A penetração do ETO no tumor foi maior na periferia (61 ± 15 % e 61 ± 29 %) do que no centro do tumor (34 ± 6 % e 28 ± 11 %) após administração das doses 10 e 20 mg/kg, respectivamente (ANOVA, α = 0.05). Um modelo de 4 compartimentos compreendendo uma distribuição saturável (cinética de Michaelis-Menten) nos compartimentos tumorais a partir do compartimento central modelou simultaneamente os perfis de concentração-tempo do ETO em plasma e em ambas regiões do tumor. O modelo populacional PK/PD Simeoni TGI–Emax foi capaz de descrever o efeito antitumoral dependente do regime de administração do ETO utilizando concentrações totais plasmáticas ou livres no tumor, resultando em um maior k2max (potência máxima) para as concentrações livres (25,8 mL.μg-1.dia-1 - intratumoral vs. 12,6 mL.μg-1.dia-1 - plasma total). Conclusões: Os resultados mostram que a utilização das concentrações livres do fármaco no tumor para a modelagem PK/PD pode fornecer um melhor entendimento da relação farmacocinética e farmacodinâmica e melhoram a capacidade de previsão do modelo, considerando que a eficácia dos fármacos antineoplásicos no tratamento de tumores sólidos é dependente da capacidade do fármaco em se distribuir no tecido tumoral.Objective: The aim of this study was to describe the relationship between total plasma and free interstitial tumor etoposide (ETO) concentrations and the drug tumor growth inhibition observed in a Walker-256 (W256) tumor-bearing Wistar rat model using the pharmacokinetic/pharmacodynamic (PK/PD) modeling. Methods: The experiments with animals were approved by CEUA/UFRGS (protocol number 22302). Pharmacokinetic experiments were conducted to determine total plasma and free intratumoral concentrations in two regions of W256 solid tumor by microdialysis. After administration of ETO 10 or 20 mg/kg i.v. bolus to W256 tumorbearing Wistar rats, blood and tissue microdialysate samples from tumor center and periphery were simultaneously collected up to 7h to determine the tumor penetration factor. An analytical HPLC-UV method was developed and validated for quantification of ETO in plasma and microdialysate samples. The pharmacodynamic experiments were conducted in W256 tumor-bearing rats that received ETO 5 or 10 mg/kg i.v. bolus every day for 8 and 4 days, respectively. Tumor volumes were monitored daily for 30 days. Non-compartmental analysis of PK data was performed in WinNonlin®. The PK and PK/PD modeling by population approach were performed using Monolix®. PK/PD data were analyzed using a modification of Simeoni TGI model by introducing an Emax function to describe the nonlinear relationship between tumor and plasma concentrations and effect. Results and Discussion: The HLPCUV method was developed and validated to determine plasma and tissue samples of ETO. ETO tumor penetration was higher in the tumor periphery (61 ± 15 % and 61 ± 29 %) than center (34 ± 6 % and 28 ± 11 %) following 10 and 20 mg/kg doses, respectively (ANOVA, α = 0.05). A 4-compartment structural model comprising a saturable distribution (Michaelis-Menten kinetics) into the tumor compartments from the central compartment simultaneously described the ETO concentration–time profiles in plasma and both tumor regions. The PK/PD population Simeoni TGI–Emax model was capable of describing the schedule-dependent antitumor effects of ETO using total plasma or free tumor concentrations obtained in a W256-tumor bearing Wistar rat model, resulting in higher k2max (maximal potency) for free concentrations (25.8 mL.μg-1.day-1 - intratumoral vs. 12.6 mL.μg-1.day-1 total plasma). Conclusions: The results showed that the use of free intratumoral drug concentrations in the PK/PD modeling can provide a better understanding of the pharmacokinetics and pharmacodynamics relationship and improve the forecasting ability of the models considering that the efficacy of antineoplastic drugs in the treatment of solid tumors is dependent on the drug ability to distribute into the tumor.
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Reddingius, Wieb Reddingius Wiebrandus Gerardus. "Bioanalysis and pharmacokinetics of fumarates in humans /". [S.l.] : [s.n.], 1997. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=12199.
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30
Hu, Leijun. "Suramin pharmacokinetics after regional or systemic administration". Connect to resource, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1114449390.
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31
Hasegawa, Takaaki, Kenji Takagi e Kiyoyuki Kitaichi. "Effects of Bacterial Endotoxin on Drug Pharmacokinetics". 名古屋大学医学部, 1999. http://hdl.handle.net/2237/6203.
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32
Penson, Richard Thomas. "The morphine glucuronides : pharmacokinetics, pharmacodynamics and interactions". Thesis, Queen Mary, University of London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406201.
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33
Pullen, Joyce. "Pharmacokinetics and dosing of antibiotics in neonates". [Maastricht] : Maastricht : Universitaire Pers Maastricht ; University Library, Universiteit Maastricht [host], 2007. http://arno.unimaas.nl/show.cgi?fid=8305.
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34
Ekborn, Andreas. "Cisplatin induced ototoxicity : pharmacokinetics, prediction and prevention /". Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-721-5.
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35
Turner, Joe. "Application of artificial neural networks in pharmacokinetics /". Connect to full text, 2003. http://setis.library.usyd.edu.au/adt/public_html/adt-NU/public/adt-NU20031007.090937/index.html.
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Chan, Hui Min Ravis William R. "Pharmacokinetics of Voriconazole in horses and alpacas". Auburn, Ala, 2008. http://repo.lib.auburn.edu/EtdRoot/2008/SPRING/Pharmacal_Sciences/Dissertation/Chan_Hui_20.pdf.
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37
Rahman, Nargis Jahan. "Incorporation of population pharmacokinetics into drug development". Thesis, Imperial College London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325239.
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38
Konsue, Nattaya. "Pharmacokinetics and chemopreventive potential of phenethyl isothiocyanate". Thesis, University of Surrey, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.511107.
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39
李富榮 e Foo-wing Lee. "Pharmacokinetics of homoharringtonine in Chinese leukemia patients". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1990. http://hub.hku.hk/bib/B31209233.
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40
Davies, Geraint Rhys. "Pharmacokinetics and pharmacodynamics of anti-tuberculosis chemotherapy". Thesis, University of Liverpool, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.502576.
Testo completoAbstract (sommario):
For the first time in thirty years the tuberculosis drug development pipeline may be on the verge of delivering ultra-short course chemotherapy but continued reliance on relapse rates in clinical trials and limited understanding ofthe phenomenon ofpersistence ofM tuberculosis during treatment have made the critical pathway of early clinical development uncertain. It is demonstrated here that serial sputum colony counting,prolonged throughout the first two months oftreatment and analysed using hierarchical non-linear regression techniques has the power to detect treatment differences between combination drug regimens at very modest sample sizes.
41
Al-Mehsen, Fahad A. "Clinical pharmacokinetics of antibiotics in cystic fibrosis". Thesis, Queen's University Belfast, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336044.
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42
Chen, An Ge. "The pharmacokinetics of imipramine in Chinese subjects". Thesis, Liverpool John Moores University, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.298148.
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43
Lankford, William Timothy. "The toxicity and pharmacokinetics of pyrethroid microemulsions". Thesis, Nottingham Trent University, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.384861.
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44
Kamali, F. "Metabolism and pharmacokinetics of paracetamol in man". Thesis, University of Nottingham, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.355292.
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45
Chan, E. W.-Y. "Warfarin : Stereochemical aspects of pharmacokinetics and response". Thesis, University of Manchester, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.374525.
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46
Wattanatorn, Wiboon. "Pharmacokinetics of 5-fluorouracil in cancer patients". Thesis, Robert Gordon University, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.389482.
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47
Catterall, Fenton Scott. "The biological activity and pharmacokinetics of polyphenols". Thesis, University of Surrey, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.365156.
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48
Devine, Elizabeth P. "Pharmacokinetics of intramuscular morphine in the horse". Kansas State University, 2012. http://hdl.handle.net/2097/13864.
Testo completoAbstract (sommario):
Master of ScienceDepartment of Clinical Sciences
Warren L. Beard
Pharmacokinetics of Intramuscular Morphine in the Horse Elizabeth Devine, DVM; Butch KuKanich, DVM, PhD, DACVCP; Warren Beard, DVM, MS, DACVS Objective - To determine the pharmacokinetics of morphine after intramuscular administration in a clinical population of horses Design – Prospective, clinical study Animals – Pilot study included 2 normal horses and the clinical study included 75 horses Procedures – Morphine was administered at 0.1mg/kg, IM and 2-3 blood samples were obtained from each horse at various times from 0-9 hours after administration. Plasma morphine concentrations were measured using liquid chromatography and mass spectrometry. Results – Data was analyzed using a naïve pooled pharmacokinetic model. The half-life for the elimination phase was approximately 1.5 hours, the volume of distribution (per bioavailability) was approximately 4.5 L/kg and the clearance (per bioavailability) was approximately 35 mL/kg/min. The peak plasma concentration was 21.6 ng/mL and occurred approximately 4 minutes after administration. Plasma concentrations of morphine were below the limit of quantification by 7 hours in 74 horses. Conclusions and Clinical Relevance – The relatively short half-life of morphine indicates the need for frequent dosing to maintain targeted plasma concentrations. Adverse effects were uncommon in this study and morphine was well tolerated at a dose of 0.1 mg/kg, IM. Morphine may be a useful adjunctive therapy in painful horses, but the variable plasma concentrations suggest the dose and dosing interval may need to be adjusted to the individual patient’s response.
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Merhar, Stephanie L. M. D. "Pharmacokinetics of levetiracetam in neonates with seizures". University of Cincinnati / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1305030096.
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50
Gordon, Bentley Horatio. "The pharmacokinetics and metabolism of almitrine bismesylate". Thesis, University of Leicester, 1995. http://hdl.handle.net/2381/34361.
Testo completoAbstract (sommario):
Almitrine Bismesylate (ABM) is a highly lipophillic compound of molecular weight 669.7, under development as a peripheral chemoreceptor stimulant in the treatment of chronic bronchitis and emphysema. Its pharmacokinetics and metabolism were investigated in animals and man. Following oral administration of [14C]-ABM, absorption of radioactivity is rapid and variable in man, rat, rabbit and dog. Plasma levels of radioactivity decline rapidly after both oral and intravenous administration, suggesting rapid uptake into tissues. A high affinity of almitrine for the carotid body of the urethane-anaesthetised rat confirms a prolonged and specific action of the compound. Elimination of radioactivity is slow and mainly faecal and independent of administration route or species. Recovery of the adminstered radioactivity is incomplete in all other species except rat and in man, only 86 to 94% of the administered dose was recovered in 140 days. This slow elimination may be due to repeated gut secretion and reabsorption of almitrine. Almitrine is metabolised by oxidation and N-dealkylation of the allyl side chain to form, respectively, the di- and tetrahydroxy almitrine and mono and di-deallyl almitrine with the corresponding dihydroxy monodeallyl almitrine. The major faecal metabolite in all species is tetrahydroxy almitrine (not found in plasma) and all species had qualitatively similar metabolic patterns to man both in-vivo and in-vitro from liver microsomes. The pharmacokinetics of unchanged almitrine in man shows a rapid absorption from both solution and tablet formulations. Absorption is increased (48%) in the presence of food and bioavailability is high (74%). A large volume of distribution (3100 litres) and low clearance (64ml.min-1) are consistent with a long half-life (614 to 1164h). Plasma protein binding is high (99%) in all species and is not affected by drugs likely to be coadministered with almitrine. Clinically, there is a relationship between almitrine plasma concentration and changes in Pa02 from baseline during repeated administration. Some patients with high plasma levels of almitrine (>300ng.ml-1) experienced peripheral paresthesia which is reversible. Using simulations, dosage adjustments have shown that it is possible to maintain therapeutic levels of almitrine without side effects.