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Auswahl der wissenschaftlichen Literatur zum Thema „First in vivo pharmacokinetic experiment“
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Zeitschriftenartikel zum Thema "First in vivo pharmacokinetic experiment"
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Denninger, Alexander, Ulrich Westedt und Karl G. Wagner. „Shared IVIVR for Five Commercial Enabling Formulations Using the BiPHa+ Biphasic Dissolution Assay“. Pharmaceutics 13, Nr. 2 (22.02.2021): 285. http://dx.doi.org/10.3390/pharmaceutics13020285.
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The present study intended to confirm the in vivo relevance of the BiPHa+ biphasic dissolution assay using a single set of assay parameters. Herein, we evaluated five commercial drug products formulated by various enabling formulation principles under fasted conditions using the BiPHa+ assay. The in vitro partitioning profiles in the organic phase were compared with human pharmacokinetic data obtained from literature. In the first part, a meaningful in vitro dose of the formulations was assessed by determining the maximum drug concentration in the artificial absorption sink during dissolution (organic 1-decanol layer, Cdec,max). Then, the maximum concentration of the partitioned drug in the organic layer was correlated with the in vivo fraction absorbed, which was derived from published human pharmacokinetic data. Fraction absorbed represents the percentage, which is absorbed from the intestine without considering first pass. It was found that the maximum drug concentration in the organic phase obtained from an in vitro dose of ten milligrams, which is equivalent to 15–25 µmol of the respective drug, led to the highest congruency with the fraction absorbed in vivo. In the second part, the in vivo relevance of the BiPHa+ dissolution data was verified by establishing a shared in vitro/in vivo relationship including all formulations. Based on the in vitro kinetics of the BiPHa+ experiments human in vivo plasma profiles were predicted using convolutional modelling approach. Subsequently, the calculated pharmacokinetic profiles were compared with in vivo performance of the studied drug products to assess the predictive power of the BiPHa+ assay. The BiPHa+ assay demonstrated biorelevance for the investigated in vitro partitioning profiles using a single set of assay parameters, which was verified based on human pharmacokinetic data of the five drug products.
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den Hollander, Jan G., Jenny D. Knudsen, Johan W. Mouton, Kurt Fuursted, Niels Frimodt-Møller, Henri A. Verbrugh und Frank Espersen. „Comparison of Pharmacodynamics of Azithromycin and Erythromycin In Vitro and In Vivo“. Antimicrobial Agents and Chemotherapy 42, Nr. 2 (01.02.1998): 377–82. http://dx.doi.org/10.1128/aac.42.2.377.
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ABSTRACT In this study, we determined the efficacy of various dosing regimens for erythromycin and azithromycin against four pneumococci with different susceptibilities to penicillin in an in vitro pharmacokinetic model and in a mouse peritonitis model. The MIC was 0.03 μg/ml, and the 50% effective doses (determined after one dose) of both drugs were comparable for the four pneumococcal strains and were in the range of 1.83 to 6.22 mg/kg. Dosing experiments with mice, using regimens for azithromycin of one to eight doses/6 h, showed the one-dose regimen to give the best result; of the pharmacodynamic parameters tested (the maximum drug concentration in serum [C max], the times that the drug concentration in serum remained above the MIC and above the concentration required for maximum killing, and the area under the concentration time curve),C max was the best predictor of outcome. The bacterial counts in mouse blood or peritoneal fluid during the first 24 h after challenge were not correlated to survival of the mice. The serum concentration profiles obtained with mice for the different dosing regimens were simulated in the in vitro pharmacokinetic model. Here as well, the one-dose regimen of azithromycin showed the best result. However, the killing curves in vivo in mouse blood and peritoneal fluid and in the vitro pharmacokinetic model were not similar. The in vitro killing curves showed a decrease of 2 log10 within 2 and 3 h for azithromycin and erythromycin, respectively, whereas the in vivo killing curves showed a bacteriostatic effect for both drugs. It is concluded that the results in terms of predictive pharmacodynamic parameters are comparable for the in vitro and in vivo models and that high initial concentrations of azithromycin favor a good outcome.
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Han, Lu-Ying, Yun-Long Wu, Chun-Yan Zhu, Cai-Sheng Wu und Chun-Rong Yang. „Improved Pharmacokinetics of Icariin (ICA) within Formulation of PEG-PLLA/PDLA-PNIPAM Polymeric Micelles“. Pharmaceutics 11, Nr. 2 (25.01.2019): 51. http://dx.doi.org/10.3390/pharmaceutics11020051.
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Icariin (ICA) is a major flavonoid that contains the active compound Epimedii Folium. However, ICA’s pharmacokinetic characteristics remain unsatisfactory due to its low bioavailability, and hence limited drugability. In order to improve its pharmacokinetics and achieve prolonged blood circulation time, a novel polymeric micelle, made of the self-assembled micelle between poly (ethylene glycol)-poly (L-lactic acid) (PEG-PLLA) and poly (D-lactic acid)-poly(N-isopropylacrylamide) (PDLA-PNIPAM), was designed to encapsulate ICA. Our experimental results showed that this polymeric micelle formulation of ICA exhibited uniform nano-size distribution and high stability within 48 h. The new formulation also allowed sustained ICA release in an in vitro drug release study. Furthermore, in vivo experiments revealed that ICA bioavailability in the PEG-PLLA/PDLA-PNIPAM polymeric micelle formulation was significantly higher compared to ICA alone, or ICA in the traditional Pluronic F127 micelle formulation. Finally, we show that metabolite analysis confirmed that ICA within the PEG-PLLA/PDLA-PNIPAM polymeric micelle formulation provided better drug protection, reduced drug metabolites production, and decreased undesired first-pass effects. Overall, these data show that ICA within PEG-PLLA/PDLA-PNIPAM polymeric micelle formulation exhibit advantages, in terms of improved physicochemical properties, sustained release of ICA in vitro, and improved bioavailability of ICA in vivo, which represent a feasible approach for improving the drugability of pharmaceutical small molecules with low bioavailability or poor stability.
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Michelet, Robin, Moreno Ursino, Sandrine Boulet, Sebastian Franck, Fiordiligie Casilag, Mara Baldry, Jens Rolff et al. „The Use of Translational Modelling and Simulation to Develop Immunomodulatory Therapy as an Adjunct to Antibiotic Treatment in the Context of Pneumonia“. Pharmaceutics 13, Nr. 5 (22.04.2021): 601. http://dx.doi.org/10.3390/pharmaceutics13050601.
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The treatment of respiratory tract infections is threatened by the emergence of bacterial resistance. Immunomodulatory drugs, which enhance airway innate immune defenses, may improve therapeutic outcome. In this concept paper, we aim to highlight the utility of pharmacometrics and Bayesian inference in the development of immunomodulatory therapeutic agents as an adjunct to antibiotics in the context of pneumonia. For this, two case studies of translational modelling and simulation frameworks are introduced for these types of drugs up to clinical use. First, we evaluate the pharmacokinetic/pharmacodynamic relationship of an experimental combination of amoxicillin and a TLR4 agonist, monophosphoryl lipid A, by developing a pharmacometric model accounting for interaction and potential translation to humans. Capitalizing on this knowledge and associating clinical trial extrapolation and statistical modelling approaches, we then investigate the TLR5 agonist flagellin. The resulting workflow combines expert and prior knowledge on the compound with the in vitro and in vivo data generated during exploratory studies in order to construct high-dimensional models considering the pharmacokinetics and pharmacodynamics of the compound. This workflow can be used to refine preclinical experiments, estimate the best doses for human studies, and create an adaptive knowledge-based design for the next phases of clinical development.
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ten Hoope, Werner, Markus W. Hollmann, Kora de Bruin, Hein J. Verberne, Arie O. Verkerk, Hanno L. Tan, Camiel Verhamme et al. „Pharmacodynamics and Pharmacokinetics of Lidocaine in a Rodent Model of Diabetic Neuropathy“. Anesthesiology 128, Nr. 3 (01.03.2018): 609–19. http://dx.doi.org/10.1097/aln.0000000000002035.
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Abstract Background Clinical and experimental data show that peripheral nerve blocks last longer in the presence of diabetic neuropathy. This may occur because diabetic nerve fibers are more sensitive to local anesthetics or because the local anesthetic concentration decreases more slowly in the diabetic nerve. The aim of this study was to investigate both hypotheses in a rodent model of neuropathy secondary to type 2 diabetes. Methods We performed a series of sciatic nerve block experiments in 25 Zucker Diabetic Fatty rats aged 20 weeks with a neuropathy component confirmed by neurophysiology and control rats. We determined in vivo the minimum local anesthetic dose of lidocaine for sciatic nerve block. To investigate the pharmacokinetic hypothesis, we determined concentrations of radiolabeled (14C) lidocaine up to 90 min after administration. Last, dorsal root ganglia were excised for patch clamp measurements of sodium channel activity. Results First, in vivo minimum local anesthetic dose of lidocaine for sciatic nerve motor block was significantly lower in diabetic (0.9%) as compared to control rats (1.4%). Second, at 60 min after nerve block, intraneural lidocaine was higher in the diabetic animals. Third, single cell measurements showed a lower inhibitory concentration of lidocaine for blocking sodium currents in neuropathic as compared to control neurons. Conclusions We demonstrate increased sensitivity of the diabetic neuropathic nerve toward local anesthetics, and prolonged residence time of local anesthetics in the diabetic neuropathic nerve. In this rodent model of neuropathy, both pharmacodynamic and pharmacokinetic mechanisms contribute to prolonged nerve block duration.
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Zhou, Zexun, John H. Rodman, Patricia M. Flynn, Brian L. Robbins, Carrie K. Wilcox und David Z. D'Argenio. „Model for Intracellular Lamivudine Metabolism in Peripheral Blood Mononuclear Cells Ex Vivo and in Human Immunodeficiency Virus Type 1-Infected Adolescents“. Antimicrobial Agents and Chemotherapy 50, Nr. 8 (August 2006): 2686–94. http://dx.doi.org/10.1128/aac.01637-05.
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ABSTRACT The pharmacologic variability of nucleoside reverse transcriptase inhibitors such as lamivudine (3TC) includes not only systemic pharmacokinetic variability but also interindividual differences in cellular transport and metabolism. A modeling strategy linking laboratory studies of intracellular 3TC disposition with clinical studies in adolescent patients is described. Data from ex vivo laboratory experiments using peripheral blood mononuclear cells (PBMCs) from uninfected human subjects were first used to determine a model and population parameter estimates for 3TC cellular metabolism. Clinical study data from human immunodeficiency virus type 1-infected adolescents were then used in a Bayesian population analysis, together with the prior information from the ex vivo analysis, to develop a population model for 3TC systemic kinetics and cellular kinetics in PBMCs from patients during chronic therapy. The laboratory results demonstrate that the phosphorylation of 3TC is saturable under clinically relevant concentrations, that there is a rapid equilibrium between 3TC monophosphate and diphosphate and between 3TC diphosphate and triphosphate, and that 3TC triphosphate is recycled to 3TC monophosphate through a 3TC metabolite that remains to be definitively characterized. The resulting population model shows substantial interindividual variability in the cellular kinetics of 3TC with population coefficients of variation for model parameters ranging from 47 to 87%. This two-step ex vivo/clinical modeling approach using Bayesian population modeling of 3TC that links laboratory and clinical data has potential application for other drugs whose intracellular pharmacology is a major determinant of activity and/or toxicity.
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Drăgan, Maria, Cătălina Daniela Stan, Andreea Teodora Iacob, Oana Maria Dragostin, Mihaela Boancă, Cătălina Elena Lupuşoru, Carmen Lăcrămioara Zamfir und Lenuţa Profire. „Biological Evaluation of Azetidine-2-One Derivatives of Ferulic Acid as Promising Anti-Inflammatory Agents“. Processes 8, Nr. 11 (02.11.2020): 1401. http://dx.doi.org/10.3390/pr8111401.
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The purpose of this study was to evaluate the in vivo biological potential of new azetidine-2-one derivatives of ferulic acid (6a–f). First, the in vivo acute toxicity of azetidine-2-one derivatives of ferulic acid on Swiss white mice was investigated and, based on the obtained results, it can be stated that the studied derivatives belong to compounds with moderate toxicity. The in vivo anti-inflammatory potential of these derivatives was determined in a model of acute inflammation induced by carrageenan in rats and in a chronic inflammation model induced in rats using the granuloma test. In the acute inflammation model, all the studied compounds had a maximum anti-inflammatory effect 24 h after administration, which suggests that these compounds may be classified, from a pharmacokinetic point of view, in the category of long-acting compounds. The most active compound in the series was found to be compound 6b. In the case of the chronic inflammation model, it was observed that the studied compounds (6a–f) reduced the formation of granulation tissue compared to the control group, having an intense effect of inhibiting the proliferative component. The most important inhibitory effect of inhibiting the proliferative component was recorded for compound 6b. Additionally, the investigation of liver function was performed by determining the serum levels of liver enzymes aspartate transaminase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and bilirubin (total and direct). The results showed that, in the series of azetidin-2-one derivatives, the liver enzymes concentration values were close to those recorded for the reference anti-inflammatories (diclofenac sodium and indomethacin) and slightly higher compared to the values for the healthy control group. At the end of the experiment, the animals were euthanized and fragments of liver, lung, and kidney tissue were taken from all groups in the study. These were processed for histopathological examination, and we noticed no major changes in the groups treated with the azetidine 2-one derivatives of ferulic acid compared to the healthy groups.
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Manduru, M., L. B. Mihm, R. L. White, L. V. Friedrich, P. A. Flume und J. A. Bosso. „Comparative bactericidal activity of ceftazidime against isolates of Pseudomonas aeruginosa as assessed in an in vitro pharmacodynamic model versus the traditional time-kill method.“ Antimicrobial Agents and Chemotherapy 41, Nr. 11 (November 1997): 2527–32. http://dx.doi.org/10.1128/aac.41.11.2527.
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Bactericidal activity, historically assessed by in vitro tests which employ fixed drug concentrations, may also be evaluated in in vitro pharmacodynamic models in which in vivo pharmacokinetics and bacterial growth conditions can be simulated. However, systematic comparisons between the two methods are lacking. We evaluated the bactericidal activities of ceftazidime, at two different concentration/MIC ratios (C/MICs), against 10 clinical isolates of Pseudomonas aeruginosa in a two-compartment model with continuous-infusion conditions and a 2-h half-life. These values were compared to those determined by traditional 24-h time-kill (TTK) methods at the same C/MICs. Bactericidal activities were compared by using area under the colony count-time curves. Antibiotic exposure (area under the drug concentration-time curve) was also evaluated. Although bactericidal activity appeared greater by the TTK method (P = 0.05), when it was normalized for drug exposure, these differences disappeared (P = 0.2). This disparity was likely due to differences in drug exposure in the TTK method and in the peripheral compartment of the model (site of bacteria) over the first 8 h of the experiment, during which the antibiotic accumulated to target concentrations. This suggests that the bactericidal effects with constant antibiotic concentrations are similar in the two methods; however, this may not hold true with fluctuating drug concentrations. Further, results from the pharmacodynamic model may theoretically be more relevant, as in vivo pharmacokinetics and bacterial growth conditions call be more faithfully simulated.
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Koopmans, R., F. J. Hoek, S. J. H. van Deventer und T. van der Poll. „Model for Whole Body Production of Tumour Necrosis Factor-α in Experimental Endotoxaemia in Healthy Subjects“. Clinical Science 87, Nr. 4 (01.10.1994): 459–65. http://dx.doi.org/10.1042/cs0870459.
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1. Tumour necrosis factor-α is considered an important mediator in the pathophysiology of several diseases. Although much information is available about the serum concentrations of this cytokine in these illnesses, little is known about the production of tumour necrosis factor-α in disease in vivo. 2. In the present study we aimed to estimate the extent and the kinetics of whole body tumour necrosis factor-α synthesis in experimental endotoxaemia in six healthy humans. For this purpose we first examined the pharmacokinetic behaviour of an intravenously injected bolus of recombinant human tumour necrosis factor-α (50 μg/m2) in another group of six normal subjects. We then calculated the total amount of tumour necrosis factor-α produced after intravenous injection of endotoxin (2 ng/kg) as the product of the systemic clearance of recombinant human tumour necrosis factor-α (9.5 ± 5.0 ml min−1 kg−1) and the area under the tumour necrosis factor-α concentration-time curves in the endotoxaemic subjects. 3. Recombinant human tumour necrosis factor-α showed evident two-compartment kinetics with an initial rapid disappearance (t1/2 5.1 ± 2.2 min) and a terminal slower elimination (t1/2 49 ± 5 min). Tumour necrosis factor-α synthesis after endotoxin varied markedly between individuals, ranging from 11.8 to 114.1 μg (52.7 ± 34.7 μg). The changes in time of the serum concentrations of tumour necrosis factor-α after administration of endotoxin could be accurately described with an adapted two-compartment open model that incorporated both rapid tumour necrosis factor-α production (74% of the total amount) and slow tumour necrosis factor-α production (26%). 4. Our results suggest that, in endotoxaemia, circulating tumour necrosis factor-α originates from two different sources, one in rapid and one in slow equilibrium with the circulation. We propose that the pharmacokinetic characteristics of intravenous recombinant human tumour necrosis factor-α may be used to estimate the production of rumour necrosis factor-α in clinical disease.
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Agudelo, M., und O. Vesga. „Therapeutic Equivalence Requires Pharmaceutical, Pharmacokinetic, and Pharmacodynamic Identities: True Bioequivalence of a Generic Product of Intravenous Metronidazole“. Antimicrobial Agents and Chemotherapy 56, Nr. 5 (13.02.2012): 2659–65. http://dx.doi.org/10.1128/aac.06012-11.
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ABSTRACTAnimal models of infection have been used to demonstrate the therapeutic failure of “bioequivalent” generic products, but their applicability for this purpose requires the accurate identification of those products that are truly bioequivalent. Here, we present data comparing one intravenous generic product of metronidazole with the innovator product in a neutropenic mouse thigh anaerobic infection model. Simultaneous experiments allowed comparisons (generic versus innovator) of potency and the concentration of the active pharmaceutical ingredient (API), analytical chemistry (liquid chromatography/mass spectrometry [LC/MS]),in vitrosusceptibility testing, single-dose serum pharmacokinetics (PK) in infected mice, andin vivopharmacodynamics (PD) againstBacteroides fragilisATCC 25825 in synergy withEscherichia coliSIG-1 in the neutropenic mouse thigh anaerobic infection model. The Hill dose-response model followed by curve-fitting analysis was used to calculate and compare primary and secondary PD parameters. The generic and the innovator products were identical in terms of the concentration and potency of the API, chromatographic and spectrographic profiles, MIC and minimal bactericidal concentrations (MBC) (2.0 mg/liter), and mouse PK. We found no differences between products in bacteriostatic doses (BD) (15 to 22 mg/kg of body weight per day) or the doses needed to kill 1 log (1LKD) (21 to 29 mg/kg per day) or 2 logs (2LKD) (28 to 54 mg/kg per day) ofB. fragilisunder dosing schedules of every 12 h (q12h), q8h, or q6h. The area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) was the best PD index to predict the antibacterial efficacy of metronidazole (adjusted coefficient of determination [AdjR2] = 84.6%), and its magnitude to reach bacteriostasisin vivo(56.6 ± 5.17 h) or to kill the first (90.8 ± 9.78 h) and second (155.5 ± 22.2 h) logs was the same for both products. Animal models of infection allow a thorough demonstration of the therapeutic equivalence of generic antimicrobials.
Dissertationen zum Thema "First in vivo pharmacokinetic experiment"
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Leding, Albin. „Recommendation for first pharmacokinetic in vivo experiment design with a pharmacometric informed approach“. Thesis, Uppsala universitet, Institutionen för farmaci, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-447311.
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Tuberculosis, the leading cause of death by a single infection disease caused by bacteria, requires long treatments and the bacteria are prone to develop drug resistance. Therefore, new efficient treatment regiments needs developing, which requires new tools for drug development. A major reason for discontinuance of a drug under development is undesired pharmacokinetic properties. Therefore, it is important to have early information of this, preferably the first time the drug is tested in animals. The first in vivo pharmacokinetic experiment is often done in mice and the only information present at this stage are often in vitro values and physicochemical properties. Physiological-based pharmacokinetic modelling can be used to extrapolate from in vitro to in vivo values. From this, the first in vivo pharmacokinetic experiment can be designed, often with the goal of reducing the amount of mice. This goal is one of the three R.s and it is called Reduction. To explore the Reduction of an experiment population pharmacokinetic modelling can be utilized via exploration of the imprecision, bias and probability of an informative experiment to evaluate if a design meets the goal of Reduction. In this report a recommendation of the first in vivo pharmacokinetic experiment is presented. This is based on in vitro values and physicochemical properties that are common in anti-tuberculosis drugs. If the probability of an informative experiment is critical, a terminal sampling of 40 mice is recommended. If imprecision and bias are necessary, zipper sampling of 10 mice is recommended.
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Leding, Albin. „Optimized design recommendation for first pharmacokinetic in vivo experiments for new tuberculosis drugs using pharmacometrics modelling and simulation“. Thesis, Uppsala universitet, Institutionen för farmaci, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-447311.
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Tuberculosis, the leading cause of death by a single infection disease caused by bacteria, requires long treatments and the bacteria are prone to develop drug resistance. Therefore, new efficient treatment regiments needs developing, which requires new tools for drug development. A major reason for discontinuance of a drug under development is undesired pharmacokinetic properties. Therefore, it is important to have early information of this, preferably the first time the drug is tested in animals. The first in vivo pharmacokinetic experiment is often done in mice and the only information present at this stage are often in vitro values and physicochemical properties. Physiological-based pharmacokinetic modelling can be used to extrapolate from in vitro to in vivo values. From this, the first in vivo pharmacokinetic experiment can be designed, often with the goal of reducing the amount of mice. This goal is one of the three R.s and it is called Reduction. To explore the Reduction of an experiment population pharmacokinetic modelling can be utilized via exploration of the imprecision, bias and probability of an informative experiment to evaluate if a design meets the goal of Reduction. In this report a recommendation of the first in vivo pharmacokinetic experiment is presented. This is based on in vitro values and physicochemical properties that are common in anti-tuberculosis drugs. If the probability of an informative experiment is critical, a terminal sampling of 40 mice is recommended. If imprecision and bias are necessary, zipper sampling of 10 mice is recommended.
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Thörn, Helena Anna. „First-pass Intestinal Metabolism of Drugs : Experiences from in vitro, in vivo and simulation studies“. Doctoral thesis, Uppsala universitet, Institutionen för farmaci, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-165514.
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The bioavailability of a drug can be described as the fraction of an orally administered dose that reaches the systemic circulation and is often limited by first-pass metabolism in the gut and the liver. It is important to have knowledge about these processes since the systemic blood drug concentration is tightly connected to the effect of the drug. The general aim of this project was to quantitatively examine the role of the intestine in relation to the liver in first-pass metabolism of orally administered drugs. The first-pass metabolism of verapamil and raloxifene was investigated in detail with in vivo, in vitro and simulation studies, using the pig as an experimental model. The intestine contributed to the same extent as the liver to first-pass metabolism of R/S-verapamil in vivo in pigs. The S-isomer of verapamil was found in lower plasma concentrations compared to the R-isomer after oral dosing. The in vitro metabolism of verapamil in pig and human liver showed interspecies similarity and indicated equal intrinsic clearance for R- and S-verapamil. Through physiologically based pharmacokinetic modeling the stereoselectivity was explained by a combination of several processes, including enantioselective plasma protein binding, blood-to-plasma partition, and gut and liver tissue distribution. For raloxifene the intestine was the dominating organ in first-pass glucuronidation in vivo in pigs. Furthermore, the raloxifene concentration entering the intestine or the dose administered in the gut did not influence the plasma PK of raloxifene and indicated that the intestinal metabolism was not saturable with clinical relevant doses. For both verapamil and raloxifene, a time-dependent hepatic metabolism was noted with major consequences to the pharmacokinetic of the drugs. This project has pointed out the importance of intestinal metabolism in the overall first-pass extraction of drugs and indicates that intestinal metabolism should be considered and evaluated early in drug development.
Buchteile zum Thema "First in vivo pharmacokinetic experiment"
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Chandrasekhar, Jaya, Adriano Caixeta, Philippe Généreux, George Dangas und Roxana Mehran. „In-stent restenosis in the drug-eluting stent era“. In Oxford Textbook of Interventional Cardiology, herausgegeben von Simon Redwood, Nick Curzen und Adrian Banning, 453–72. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198754152.003.0030.
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Since the inception of percutaneous coronary intervention, restenosis has been considered a significant problem. Although drug-eluting stents (DES) have reduced rates of in-stent restenosis (ISR) compared with bare metal stents across all lesion subsets, ISR has not been abolished. DES efficacy has been limited by suboptimal polymer biocompatibility, efficacy of pharmacological agents, in vivo pharmacokinetic properties, and local drug resistance and toxicity. While the first two DES to be manufactured (sirolimus- and paclitaxel-eluting stents) have the longest clinical follow-up, extensive data are now also available on zotarolimus- and everolimus-eluting stents. The uptake of biolimus-eluting stents has recently increased in clinical practice. Although the low frequency of DES ISR makes it difficult to investigate this condition fully, many studies have examined the mechanism, incidence, predictors, and optimal treatment of DES restenosis. This review discusses the data relevant to DES restenosis and the perspective on the current treatment of this condition.
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Caixeta, Adriano, Philippe Généreux, George Dangas und Roxana Mehran. „In-stent restenosis in the drug-eluting stent era“. In Oxford Textbook of Interventional Cardiology, 486–503. Oxford University Press, 2010. http://dx.doi.org/10.1093/med/9780199569083.003.028.
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For the last two decades, restenosis has been considered the most significant problem in interventional cardiology. Drug-eluting stents (DES) have reduced rates of restenosis and target lesion revascularization (TLR) by 50–90% compared with bare-metal stents (BMS) across all lesion and patient subsets. However, a small number of patients have in-stent restenosis (ISR) after DES treatment. DES efficacy has been limited by suboptimal polymer biocompatibility, suitability of pharmacological agents, suboptimal in vivo pharmacokinetic properties, and local drug resistance and toxicity. The first two DES (sirolimus-eluting stents [SES] and paclitaxel- eluting stents [PES]) have the longest clinical follow- up, whereas the zotarolimus-eluting stents [ZES], everolimus-eluting stents [EES], and biolimus-eluting stents [BES] have only recently been introduced in daily practice. Although the low frequency of ISR events with DES makes it difficult to fully investigate this syndrome, many studies have been conducted or are ongoing to find the mechanism, incidence, predictors, and optimal treatment of DES restenosis. This review discusses the data relevant to DES restenosis and the perspective on the current treatment of this condition.
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Hasty, Paul, und Alejandro Abuin. „Gene targeting, principles, and practice in mammalian cells“. In Gene Targeting. Oxford University Press, 1999. http://dx.doi.org/10.1093/oso/9780199637928.003.0005.
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When a fragment of genomic DNA is introduced into a mammalian cell it can locate and recombine with the endogenous homologous sequences. This type of homologous recombination, known as gene targeting, is the subject of this chapter. Gene targeting has been widely used, particularly in mouse embryonic stem (ES) cells, to make a variety of mutations in many different loci so that the phenotypic consequences of specific genetic modifications can be assessed in the organism. The first experimental evidence for the occurrence of gene targeting in mammalian cells was made using a fibroblast cell line with a selectable artificial locus by Lin et al. (1), and was subsequently demonstrated to occur at the endogenous β-globin gene by Smithies et al. in erythroleukaemia cells (2). In general, the frequencies of gene targeting in mammalian cells are relatively low compared to yeast cells and this is probably related to, at least in part, a competing pathway: efficient integration of the transfected DNA into a random chromosomal site. The relative ratio of targeted to random integration events will determine the ease with which targeted clones are identified in a gene targeting experiment. This chapter details aspects of vector design which can determine the efficiency of recombination, the type of mutation that may be generated in the target locus, as well as the selection and screening strategies which can be used to identify clones of ES cells with the desired targeted modification. Since the most common experimental strategy is to ablate the function of a target gene (null allele) by introducing a selectable marker gene, we initially describe the vectors and the selection schemes which are helpful in the identification of recombinant clones (Sections 2-5). In Section 6, we describe the vectors and additional considerations for generating subtle mutations in a target locus devoid of any exogenous sequences. Finally, Section 7 is dedicated to the use of gene targeting as a method to express exogenous genes from specific endogenous regulatory elements in vivo, also known as ‘knock-in’ strategies. A targeting vector is designed to recombine with and mutate a specific chromosomal locus.
Konferenzberichte zum Thema "First in vivo pharmacokinetic experiment"
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Albada, J., K. K. Nieuwenhuis und J. J. Sixma. „PHARMACOKINETICS OF A LOW MOLECULAR WEIGHT HEPARIN (KABI 2165, FRAGMIN) ATFER INTRAVENOUS AND SUBCUTANEOUS ADMINISTRATION IN HUMAN VOLUNTEERS AND ITS IN VIVO NEUTRALIZATION BY PROTAMINE SULFATE“. In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1642866.
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Pharmacokinetics of a low molecular weight heparin (LMWH) were studied in healthy volunteers. After an intravenous bolus injection of 5000 anti-Xa U in 5 healthy volunteers anti Xa activity disappeared according to the combination of saturable and a linear mechanism, preceded by a rapid initial disappearance. The apparent half-life of the anti Xa activity is about twice as long as that of standard heparin. In another set of experiments 5000 anti Xa U of LMWH were immediately followed by 50 mgr of Protamine Sulphate (PS). The curve of the anti Xa-activity parallelled the original curve at a level of about 30-40%. No rebound phenomenon was observed. The same dose of the LMWH followed by 100 mg of PS resulted in an anti Xa disappearance curve at an obvious higher level of about 50%. Also at this dose no rebound phenomenon was noticed.A continuous infusion of 10.000 anti Xa U/24 h during 10 hours was followed by 15.000 anti Xa U/24 h for another 10 hours after which the dose was raised to 20.000 anti Xa U/24 h for another 10 hours. Only the first infusion period resulted in a plateau fase. At the end of these experiments anti Xa activity was neutralized by 50 mg P.S. i.v. resulting in the disappearance of less than 50% of anti Xa activity. After subcutaneous administration of 15.000 anti Xa U (corresponding to the dose for i.v. treatment per day with this LMWH) peak levels of 1,1-1,8 anti Xa were reached after 3-4 hours. Supra-optimal anti Xa levels (higher than 0.9) were observed in all volunteers during a period of 5 hours. After 24 hours in none of the volunteers any anti Xa-activity could be detected.Conclusions:In contrast to previous reports pharmacokinetics of this LMWH do not essentially differ from those of standard heparin apart from its longer half-life and its high bioavialability after subcutaneous injection.
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Blanco, Elvin, Takafumi Sangai, Funda Meric-Bernstam und Mauro Ferrari. „Chemotherapeutic Synergy Enhancement Through Micellar Nanotherapeutics“. In ASME 2010 First Global Congress on NanoEngineering for Medicine and Biology. ASMEDC, 2010. http://dx.doi.org/10.1115/nemb2010-13263.
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Current chemotherapeutic regimens involve the administration of a combination of agents with hopes of gaining synergistic cell-killing effects observed in vitro. However, drug synergy is rarely realized clinically given the different pharmacokinetic profiles of the drugs. Recent findings show that a combination of rapamycin and paclitaxel proves highly effective at hindering growth of tumors wherein the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. Our objective was to fabricate a micellar nanotherapeutic platform capable of delivering a multitude of agents shown to synergistically affect a specific pathway (PI3K/Akt/mTOR) in breast cancer. We hypothesized that this concomitant delivery strategy will result in increased antitumor efficacy, given the site-specific and controlled delivery of the two agents. Herein, we demonstrate the successful fabrication of a nanotherepeutic strategy for the treatment of breast tumors with aberrant PI3K/Akt/mTOR pathways. Resulting polymer micelles were small in size (∼30 nm) and showed high levels of drug incorporation efficiency of both rapamycin and paclitaxel. Current studies involve the examination of release kinetics and antitumor efficacy in in vitro and in vivo models.
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Maglich, Bogdan C., und Orhan Nalcioglu. „‘ONCOSENSOR’ for Noninvasive High-Specificity Breast Cancer Diagnosis by Carbogen-Enhanced Neutron Femto-Oximetry“. In ASME 2010 First Global Congress on NanoEngineering for Medicine and Biology. ASMEDC, 2010. http://dx.doi.org/10.1115/nemb2010-13295.
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Based on the first experiment on Differential Femto Oximetry (Paper 13270), we conducted a computer simulated study of the feasibility of conceptual design for our noninvasive malignancy probe, Oncosensor, to diagnose hypoxia of malignancy M = −0.90, measured by pO2 — which correspond to volume averaged hypoxia M′ = −0.09 — in 1cm, 3 cm and 5 cm DIA tumors embedded in the middle of a 10 cm DIA breast. M′ is further masked by background γ’s from the in vivo tissue by factor x = 4.4–7 for subcutaneous and central tumor, respectively, to apparent M″ = M′/X which, in turn, renders hypoxia non-diagnosable for 1 cm tumors; marginally so for 3 cm ones with specificity S = 75%, and fully diagnosable with S = 95% in 5 cm ones. To diagnose 1–3 cm and smaller tumors, we propose to enhance M″ by a factor of ≈ 3 by replacing air breathing with that of Carbogen (O2 95%, CO2 5%). With carbogen breathing, simulations predict hypoxia detection in 1 cm subcutaneous tumor with S = 68%, and in 3 cm ones with S = 95–99.9%. Carbogen renders possible 2 additional diagnostic tests for redundancy. Significant improvements of the above measurement accuracies are projected. Oncosensor will be tested in vivo with R3230 tumors in Fischer rats at UCI’s Center for Functional Onco-Imaging. Oncosensor requires imaging guidance.
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Skulborstad, A. J., und N. C. Goulbourne. „Biaxial Mechanical Characterization of Bat Wing Skin and Development of Biomimetic Constructs“. In ASME 2013 Conference on Smart Materials, Adaptive Structures and Intelligent Systems. American Society of Mechanical Engineers, 2013. http://dx.doi.org/10.1115/smasis2013-3190.
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The highly flexible and extensible wing skin of bats enables various wing shapes and flight modes, which distinguishes it from all other natural flyers making bats an ideal model for micro-aerial vehicles. We propose that an understanding of the relationship between the structure, properties and function of the wing tissue is essential to replicate and utilize the bat’s natural capabilities. In this work, we present the first biaxial mechanical characterization of bat wing skin, identify key mechanisms in its deformation, and employ these concepts to fabricate biomimetic skins. Ten Glossophaga soricina bat specimens were available for experiment obtained from Prof. Swartz or Brown University. Of the 20 excised wing skin samples, 11 were used for establishing testing protocols, 3 tore during preparation, and 6 were tested for the characterization presented in this work. The tissue was shown to be nonlinear, heterogeneous, anisotropic, and viscoelastic. The wrinkled tissue structure and substantial anisotropy promote great spanwise deployment and deformation increasing wing area and aspect ratio enabling greater lift generation. Comparison of the material structural organization with strain field responses demonstrated that the underlying fiber architecture corresponds to observed local strain variations and that the tissue represents a departure from traditional fiber reinforced materials since the mesoscopic elastin fiber architecture appears to be the soft component while the matrix provides the stiffening role. Fabricated skins capture the inherent mismatch in natural configurations of the spanwise elastin fibers and the matrix and exhibit the characteristic wrinkle pattern observed in the in vivo bat wing skin. Future work will include static mechanical testing of the synthetic skins as well as aerodynamic testing to investigate the link between tissue structure, properties and functional flight capabilities.
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Tang, Xin, und Taher Saif. „Loss of Cell Adhesion in Colon Cancer Cells During In Vitro Metastasis Measured by Bio-MEMS Force Sensor“. In ASME 2012 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2012. http://dx.doi.org/10.1115/sbc2012-80936.
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Human colon carcinoma (HCT-8) cells show metastatic phenotype when cultured on appropriately soft substrates. Here, we studied the surface non-specific adhesion in HCT-8 cells throughout the in vitro metastasis process. A novel bio-MEMS force sensor was used to measure the cell-probe non-specific adhesion. The adhesion characteristics are analyzed using classical Johnson-Kendall-Roberts (JKR) theory. Our results indicate that the post-metastatic HCT-8 cells (dissociated R cells) display remarkably diminished surface adhesion and are potentially more invasive than original pre-metastatic HCT-8 cells (E cells). To the best of our knowledge, this is the first quantitative data on cancer cells adhesion change as in vitro metastasis proceeds. It is well known that, during in vivo cancer metastasis, malignant cancer cells reduce their surface adhesion (both specific and non-specific) [1] as well as modify their extracellular matrix (ECM) ligands [2] to detach from primary tumor and enhance successful invasion into distant healthy organs. Simultaneously, cancer cells down-regulate their surface cell-cell adhesion molecules, i.e. E-Cadherin, to escape from tumor and initiate metastasis [1]. However, there is no quantitative report on cancer cell adhesion throughout the entire metastasis process, since in vivo metastasis is nearly impossible to detect [3]. We had discovered [4] that human colon cancer cells (HCT-8) can consistently display an in vitro metastasis-like phenotype (MLP) within only 7 days of culture on soft hydrogel substrates with appropriate mechanical stiffness (Poly-acrylamide gels with Elastic modulus: 21∼ 47 kPa [14, 15]). We found that MLP is consistent, repeatable and irreversible (Fig. 1a-1c). In addition, the post MLP cancer cells (referred to here as R cells meaning round-shaped in contrast to the E-cells, i.e., the original HCT-8 cells that are epithelial in nature) up-regulate a number of in vivo tissue-destructive proteinases, such as, MMPs [4]. R cells also express remarkably diminished E-Cadherin patterns compared to HCT8 E cells (Fig. 1d, 1e). Using this model system, we are able to study the kinetics of non-specific and specific surface adhesion change on HCT-8 cancer cells. In this paper, we measure the non-specific adhesion of both pre and post metastatic HCT-8 cells (E and R cells respectively) using a novel bio-MEMS force sensor. The adhesion energy and other mechanical properties are analyzed using classical Johnson-Kendall-Roberts (JKR) theory [5]. We find that after undergoing metastasis (or MLP), the dissociated HCT-8 cells (R cells) down-regulate non-specific adhesion, in contrast to their ancestors, HCT-8 E cells. The reduction of non-specific adhesion is coincident with the immuno-fluorescent staining data of cell-cell specific adhesion molecule E-Cadherin, which shows 4 ∼ 6 times down-regulation after MLP (Fig. 1d-1e). The bio-MEMS sensor consists of a micro cantilever beam with spring constant k = 3.48 nN/ μm. A flat probe is attached with the beam which forms adhesive contact with cells. The sensor is made from single crystal silicon, and is coated with a thin layer of native silicon oxide (SiO2). The probe and the sensor are not functionalized. The sensor is manipulated with an x-y-z piezo stage. To measure the cell adhesion, the flat probe is brought in contact with cells’ lateral convex surface at the boundary. After a 2-minute contact, force sensor is pulled away horizontally from the cell island at a constant quasi-static speed of 2.1 ± 0.4 μm/s (Fig. 2a). Due to the cell-probe adhesion, the sensor beam deforms during retraction. Corresponding restoring force of the cell island is given by F = kδ (Fig. 2a-c). Note the probe is non-functionalized (free of any extra-cellular matrix proteins), and only has a coating of SiO2 on the surface due to air exposure. During probe retraction, the cell is continuously stretched while the cell-probe contact area radius Rc remains unchanged (Fig. 3b-e) and the contact angle θ increases (Fig. 3b). At critical value of force, Fc, the cell suddenly detaches from probe (Fig. 3d). The critical Fc at detachment is optically recorded by video camera and was determined as 27.8 ± 2.2 nN. A similar experiment on cells after MLP shows so measurable adhesion, i.e, the force to detach was zero for all the cells tested. Figure shows the measured adhesion in pre and post metastatic cells.