Zeitschriftenartikel: „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.

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Dehghanyar, Pejman, Cornelia Bürger, Markus Zeitlinger, Florian Islinger, Florian Kovar, Markus Müller, Charlotte Kloft und Christian Joukhadar. „Penetration of Linezolid into Soft Tissues of Healthy Volunteers after Single and Multiple Doses“. Antimicrobial Agents and Chemotherapy 49, Nr. 6 (Juni 2005): 2367–71. http://dx.doi.org/10.1128/aac.49.6.2367-2371.2005.

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ABSTRACT The present study tested the ability of linezolid to penetrate soft tissues in healthy volunteers. Ten healthy volunteers were subjected to linezolid drug intake at a dose of 600 mg twice a day for 3 to 5 days. The first dose was administered intravenously. All following doses were self-administered orally. The tissue penetration of linezolid was assessed by use of in vivo microdialysis. In the single-dose experiments the ratios of the area under the concentration-time curve from 0 to 8 h (AUC0-8) for tissue to the AUC0-8 for free plasma were 1.4 ± 0.3 (mean ± standard deviation) and 1.3 ± 0.4 for subcutaneous adipose and muscle tissue, respectively. After multiple doses, the corresponding mean ratios were 0.9 ± 0.2 and 1.0 ± 0.5, respectively. The ratios of the AUC from 0 to 24 h (AUC0-24) for free linezolid in tissues to the MIC were between 50 and 100 for target pathogens with MICs between 2 and 4 mg/liter. In conclusion, the present study showed that linezolid penetrates rapidly into the interstitial space fluid of subcutaneous adipose and skeletal muscle tissues in healthy volunteers. On the basis of pharmacokinetic-pharmacodynamic calculations, we suggest that linezolid concentrations in soft tissues can be considered sufficient to inhibit the growth of many clinically relevant bacteria.

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Sawada, Yasufumi, Ryosei Kawai, Mary McManaway, Hideo Otsuki, Kenner C. Rice, Clifford S. Patlak und Ronald G. Blasberg. „Kinetic Analysis of Transport and Opioid Receptor Binding of [3H](−)-Cyclofoxy in Rat Brain in vivo: Implications for Human Studies“. Journal of Cerebral Blood Flow & Metabolism 11, Nr. 2 (März 1991): 183–203. http://dx.doi.org/10.1038/jcbfm.1991.51.

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[3H]Cyclofoxy (CF: 17-cyclopropylmethyl-3,14-dihydroxy-4,5-α-epoxy-6-β-fluoromorphinan) is an opioid antagonist with affinity to both mu and kappa subtypes that was synthesized for quantitative evaluation of opioid receptor binding in vivo. Two sets of experiments in rats were analyzed. The first involved determining the metabolite-corrected blood concentration and tissue distribution of CF in brain 1 to 60 min after i.v. bolus injection. The second involved measuring brain washout for 15 to 120 s following intracarotid artery injection of CF. A physiologically based model (Sawada et al., 1990 a) and a classical compartmental pharmacokinetic model (Wong et al., 1986 a) were compared. The models included different assumptions for transport across the blood-brain barrier (BBB); estimates of nonspecific tissue binding and specific binding to a single opiate receptor site were found tobe essentially the same with both models. The nonspecific binding equilibrium constant varied modestly in different brain structures ( Keq = 3–9), whereas the binding potential (BP) varied over a much broader range (BP = 0.6–32). In vivo estimates of the opioid receptor dissociation constant were similar for different brain structures ( KD = 2.1–5.2 n M), whereas the apparent receptor density ( Bmax) varied between 1 (cerebellum) and 78 (thalamus) pmol/g of brain. The receptor dissociation rate constants in cerebrum ( k4 = 0.08–0.16 min−1; koff = 0.16–0.23 min−1) and brain vascular permeability ( PS = 1.3–3.4 ml/min/g) are sufficiently high to achieve equilibrium conditions within a reasonable period of time. Graphical analysis (Patlak and Blasberg, 1985) of the data is inappropriate due to the high tissue-loss rate constant ( kb = 0.03–0.07 min−1) for CF in brain. From these findings, CF should be a very useful opioid receptor ligand for the estimation of the receptor binding parameters in human subjects using [18F]CF and positron emission tomography.

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Azmanis, Panagiotis, Lucia Pappalardo, Ziad A. J. Sara, Christudas Silvanose und Vinny Naidoo. „Disposition of posaconazole after single oral administration in large falcons (Falco spp): Effect of meal and dosage and a non-compartmental model to predict effective dosage“. Medical Mycology 59, Nr. 9 (23.04.2021): 901–8. http://dx.doi.org/10.1093/mmy/myab019.

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Abstract Posaconazole has been used anecdotally to treat aspergillosis in falcons resistant to voriconazole. In human medicine, it is used prophylactically in immunosuppressed human subjects with invasive pulmonary aspergillosis. So far, no studies have been performed in birds. The aim of this study was to evaluate the in-vivo pharmacokinetic behavior of oral posaconazole after a single administration in six large falcons (i.e gyrfalcons, saker falcons). Posaconazole oral suspension (Noxafil, 40 mg/ml, Schering-Plough) was administered per os without meal in a single dosage of 12.5 mg/kg in 3 falcons. A comparison was done in two more falcons, one with a natural fatty meal at the same single dose, and one with a natural fatty meal and a higher dosage (20 mg/kg). Finally, six falcons received posaconazole pre-dissolved in corn oil with a natural low-fat meal in the higher single dose (20 mg/kg). No side effects were observed in the falcons in any of the experiments. In starved state posaconazole was poorly absorbed, more so than in other species. As expected, absorption of posaconazole was higher with the administration of meal or in the presence of plant (corn) oil, with a fourfold increase in apparent bioavailability. Despite the preferential absorption in the presence of fat, for both dosing schemes the AUC24 : MIC ratio was lower than described in human medicine to achieve a therapeutic effect. The AUCinf : MIC which is an indicator of efficacy after steady-state, while variable, did indicate that the drug is worth trying when susceptibility testing shows to be the only effective drug. Lay Abstract The focus of this work is to determine the pharmacokinetic parameters of oral posaconazole in large falcons for the first time after a single dose. Posaconazole has higher bioavailability when administered with meal and fatty components. No adverse reactions have been observed. The ratio of the area under the curve (AUC24) to minimum inhibitory concentration was lower compared to the therapeutic level in human.

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Pollak, M. N., M. Q. Lacy, A. Lipton, L. Demers, K. Leitzel, J. S. de Bono, D. Yin, L. Roberts, A. Sharma und A. Gualberto. „Pharmacodynamic properties of the anti-IGF-IR monoclonal antibody CP-751,871 in cancer patients“. Journal of Clinical Oncology 25, Nr. 18_suppl (20.06.2007): 3587. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.3587.

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3587 Background: The Insulin like Growth Factor I receptor (IGF-IR), a tyrosine kinase, is widely expressed in human tissues. IGF- IR and its ligands (IGF-I and IGF-II) are expressed by many human cancers (e.g., breast, prostate, colorectal and non-small cell lung). Binding of the ligands to the IGF-IR activates key cellular signaling pathways important for stimulating cellular proliferation and inhibiting apoptosis. IGF- I and IGF-II are present in the circulation, but also locally expressed in neoplastic tissue. Bioavailability of these ligands is regulated by a family of IGF binding proteins (IGFBPs1–6). CP-751,871, a fully human monoclonal antibody, is a highly specific and potent inhibitor of IGF-IR activation. In vitro experiments show that binding of CP 751,871 to IGF-IR induces receptor internalization and degradation. This antibody has been shown to have antineoplastic activity using both in vivo and in vitro pre-clinical models. Methods: Blood samples were collected for characterization of the pharmacokinetic and pharmacodynamic properties of CP-751,871 in phase 1 trials of this agent given to cancer patients either alone or in combination with chemotherapy. The endpoints assessed included among others: CP-751,871 plasma concentrations, total and free IGF-I, IGFBP-3, soluble IGF-IR and IGF-IR expression on granulocytes and tumor cells. Results: CP 751,871 exposure increased with dose over the 800-fold dose range investigated. Pharmacokinetic profiles were consistent with target-mediated disposition. A dose-dependent downregulation of soluble IGF-IR serum concentration and IGF-IR expression was observed, with sustained inhibition for the entire dosing period (3–4 week cycles) observed at doses ≥ 1.5 mg/kg. As predicted for an agent that interferes with IGF-I action, IGF-I and IGFBP-3 serum levels were up-regulated in a similar dose-dependent manner. Conclusions: The pharmacodynamic endpoints of clinical trials provide evidence that CP-751,871 targets IGF-IR in granulocytes, tumor cells and tissues involved in regulation of the growth hormone -IGF-I axis. These data provide proof of principle for the use of CP-751,871 as a first-in-class therapeutic approach to inhibit the IGF-IR pathway in cancer patients. No significant financial relationships to disclose.

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Sawada, Y., S. Hiraga, B. Francis, C. Patlak, K. Pettigrew, K. Ito, E. Owens et al. „Kinetic Analysis of 3-Quinuclidinyl 4-[125I]Iodobenzilate Transport and Specific Binding to Muscarinic Acetylcholine Receptor in Rat Brain in vivo: Implications for Human Studies“. Journal of Cerebral Blood Flow & Metabolism 10, Nr. 6 (November 1990): 781–807. http://dx.doi.org/10.1038/jcbfm.1990.136.

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Radioiodinated R- and S-Quinuclidinyl derivatives of RS-benzilate (R- and S-125IQNB) have been synthesized for quantitative evaluation of muscarinic acetylcholine receptor binding in vivo. Two sets of experiments were performed in rats. The first involved determining the metabolite-corrected blood concentration and tissue distribution of tracer R-IQNB (active enantiomer) and S-IQNB (inactive enantiomer) in brain 1 min to 26 h after intravenous injection. The second involved the measurement of brain tissue washout over a 2-min period after loading the brain by an intracarotid artery injection of the ligands. Various pharmacokinetic models were tested, which included transport across the blood–brain barrier (BBB), nonspecific binding, low-affinity binding, and high-affinity binding. Our analysis demonstrated that the assumptions of rapid equilibrium across the BBB and rapid nonspecific binding are incorrect and result in erroneous estimates of the forward rate constant for binding at the high-affinity receptor sites ( k3). The estimated values for influx across the BBB ( K1), the steady-state accumulation rate in cerebrum ( K), and the dissociation rate constant at the high-affinity site ( k4) of R-IQNB were independent of the specific compartmental model used to analyze these data ( K1 ≈ 0.23 ml/min/g, K ≈ 0.13 ml/ min/g, and k4 ≈ 0.0019 min− 1 for caudate). In contrast, the estimated values of k3 and the efflux rate constant ( k2) varied over a 10-fold range between different compartmental models ( k3 ≈ 2.3–22 min− 1 and k2 ≈ 1.6–16 min− 1 in caudate), but their ratios were constant ( k3/ k2 ≈ 1.4). Our analysis demonstrates that the estimates of k3 (and derived values such as the binding potential) are model dependent, that the rate of R-IQNB accumulation in cerebrum depends on transport across the BBB as well as the rate of binding, and that uptake in cerebrum is essentially irreversible during the first 360 min after intravenous administration. Graphical analysis was consistent with compartmental analysis of the data and indicated that steady-state uptake of R-IQNB in cerebrum is established within 1–5 min after intravenous injection. We propose a new approach to the analysis of R-IQNB time-activity data that yields reliable quantitative estimates of k3, k4, and the nonspecific binding equilibrium constant ( Keq) by either compartmental or graphical analysis. The approach is based on determining the free unbound fraction of radiolabeled ligand in blood and an estimate of K1. The analysis can be applied to time-activity data obtained in a clinical setting using either positron emission tomography or single photon emission computed tomography and has general application for other highly lipophilic ligands.

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Lee, Ning, Yingfu Li, Chester Yuan, Guanfeng Liu und Chunchao Yue. „Discovery of HBW-3-10: A potent, orally active, reversible Bruton’s tyrosine kinase (BTK) inhibitor with antitumor activity in mice.“ Journal of Clinical Oncology 39, Nr. 15_suppl (20.05.2021): e15062-e15062. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e15062.

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e15062 Background: The first generation irreversible BTK inhibitor ibrutinib has been approved for the treatment of B cell-related diseases, including chronic lymphocytic leukemia (CLL), for several years. However, CLL patients who used ibrutinib may develop drug resistance due to acquired mutations, in particular BTK C481S that directly impacts the binding of ibrutinib. In recent years, efforts have been made to develop the second generation reversible BTK inhibitors that are effective against both wild-type and C481S mutated B-cell malignancies. LOXO-305 and ARQ-531 are two examples of the second generation reversible BTK inhibitors in advanced clinical trials for ibrutinib-resistant CLL. Methods: New reversible BTK inhibitors were designed, synthesized and tested for enzymatic activities against wild-type and C481S-mutated BTK. Highly active compounds were confirmed for growth effects in diffuse large B-cell lymphoma derived TMD8 cells. Their microsomal stability and ADME properties were also assessed. Potent and bioavailable compounds were further evaluated in vivo efficacy using a TMD8 xenograft tumor model in mice. A 14-day toxicity study in rats was performed correspondingly. Results: As shown in the table, HBW-3-10 has greater potency and pharmacokinetic profile (rats, 10mg/kg PO) than ARQ-531. In a TMD8 mouse xenograft study, HBW-3-10, ARQ-531 and ibrutinib were compared directly, all dosed at 10mg/kg QD, and the resulting tumor growth inhibition rates (TGI) are 38.3%, 9.3% and 22.5%, respectively. Based on our data, HBW-3-10 is more efficacious than ARQ-531 and ibrutinib. In a 14-day preliminary toxicity experiment in rats, both HBW-3-10 and ARQ-531 were dosed 100mg/kg QD. Animals in ARQ531 group started showing signs of sickness on day 3, and all died on day 6 due toxicity; in contrast, no animal in HBW-3-10 group showed any sign of sickness or died during the entire course of study. Conclusions: We have discovered a novel second generation reversible BTK inhibitors HBW-3-10, that has a superior preclinical profile, efficacy and safety than other known ones. HBW-3-10 provides a valuable clinical candidate for treating Ibrutinib resistant CLL and beyond![Table: see text]

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Cianci, Christopher, Eugene V. Genovesi, Lucinda Lamb, Ivette Medina, Zheng Yang, Lisa Zadjura, Hyekyung Yang et al. „Oral Efficacy of a Respiratory Syncytial Virus Inhibitor in Rodent Models of Infection“. Antimicrobial Agents and Chemotherapy 48, Nr. 7 (Juli 2004): 2448–54. http://dx.doi.org/10.1128/aac.48.7.2448-2454.2004.

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ABSTRACT BMS-433771 is a potent inhibitor of respiratory syncytial virus (RSV) replication in vitro. Mechanism of action studies have demonstrated that BMS-433771 halts virus entry through inhibition of F protein-mediated membrane fusion. BMS-433771 also exhibited in vivo efficacy following oral administration in a mouse model of RSV infection (C. Cianci, K. Y. Yu, K. Combrink, N. Sin, B. Pearce, A. Wang, R. Civiello, S. Voss, G. Luo, K. Kadow, E. Genovesi, B. Venables, H. Gulgeze, A. Trehan, J. James, L. Lamb, I. Medina, J. Roach, Z. Yang, L. Zadjura, R. Colonno, J. Clark, N. Meanwell, and M. Krystal, Antimicrob. Agents Chemother. 48:413-422, 2004). In this report, the in vivo efficacy of BMS-433771 against RSV was further examined in the BALB/c mouse and cotton rat host models of infection. By using the Long strain of RSV, prophylactic efficacy via oral dosing was observed in both animal models. A single oral dose, administered 1 h prior to intranasal RSV inoculation, was as effective against infection as a 4-day b.i.d. dosing regimen in which the first oral dose was given 1 h prior to virus inoculation. Results of dose titration experiments suggested that RSV infection was more sensitive to inhibition by BMS-433771 treatment in the BALB/c mouse host than in the cotton rat. This was reflected by the pharmacokinetic and pharmacodynamic analysis of the efficacy data, where the area under the concentration-time curve required to achieve 50% of the maximum response was ∼7.5-fold less for mice than for cotton rats. Inhibition of RSV by BMS-433771 in the mouse is the result of F1-mediated inhibition, as shown by the fact that a virus selected for resistance to BMS-433771 in vitro and containing a single amino acid change in the F1 region was also refractory to treatment in the mouse host. BMS-433771 efficacy against RSV infection was also demonstrated for mice that were chemically immunosuppressed by cyclophosphamide treatment, indicating that compound inhibition of the virus did not require an active host immune response.

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Le Moigne, Ronan, Han-Jie Zhou, Nasrin R. Mawji, C. Adriana Banuelos, Jun Wang, Kunzhong Jian, Peter Virsik, Raymond J. Andersen und Marianne Sadar. „Next generation N-terminal domain androgen receptor inhibitors with improved potency and metabolic stability in castration-resistant prostate cancer models.“ Journal of Clinical Oncology 37, Nr. 7_suppl (01.03.2019): 220. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.220.

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220 Background: EPI-506, pro-drug of EPI-002, was a first-in-class oral small molecule from the Aniten family of compounds, which inhibit androgen receptor (AR) activity by binding to the N-terminal domain of the AR. EPI-506 was tested in a Phase 1 study in men with metastatic castration-resistant prostate cancer (mCRPC) resistant to current therapies and demonstrated a favorable tolerability profile with signs of moderate efficacy. Metabolic vulnerabilities in the chemical scaffold of EPI-506 were identified and new Aniten molecules, EPI-7170 and EPI-7245 , with improved potency, metabolic stability and pharmaceutical properties have been generated. Methods: Chemical structure activity relationships were developed in order to increase molecule potency in cellular and in vivo assays, while metabolic stability improvements were assessed in in vitro ADME assays and in animal pharmacokinetic studies. In addition, the on-target activity and selectivity was also optimized using a variety of cellular experiments. Results: Next generation Anitens demonstrated a 10-20 fold improvement on AR-driven cellular potency, with IC50’s of 0.5-1 uM when compared to 10-12 uM for EPI-002. In vitro proliferation assays demonstrated on target activity, with an IC50 ~ 2 uM in LNCaP and > 10 uM in the AR-independent cell model PC-3. EPI-7170 was also active in AR-V7-driven LNCaP95 cells. The antiproliferative effect was in alignment with the inhibitory effect on a subset of AR driven genes. In vivo activity in castrated mice bearing LNCaP tumors showed tumor growth inhibition of approximately 70%. While EPI-7170 represents a major advance, subsequent chemistry efforts led to the generation of EPI-7245 and other next generation Anitens which exhibit IC50’s < 500 nM and favorable ADME and PK profiles. Conclusions: Promising next-generation Aniten compounds have been identified. Major chemistry efforts led to the identification of several Anitens with > 10-20 fold improvements in cellular potency compared to EPI-506 which are also metabolically stable. IND-selection preclinical studies are underway on the most promising Aniten’s with an IND submission planned shortly.

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Cristani, M., A. Daducci, P. Farace, P. Marzola, V. Murino, A. Sbarbati und U. Castellani. „DCE-MRI Data Analysis for Cancer Area Classification“. Methods of Information in Medicine 48, Nr. 03 (2009): 248–53. http://dx.doi.org/10.3414/me9224.

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Summary Objectives: The paper aims at improving the support of medical researchers in the context of in-vivo cancer imaging. Morphological and functional parameters obtained by dynamic contrast-enhanced MRI (DCE-MRI) techniques are analyzed, which aim at investigating the development of tumor microvessels. The main contribution consists in proposing a machine learning methodology to segment automatically these MRI data, by isolating tumor areas with different meaning, in a histological sense. Methods: The proposed approach is based on a three-step procedure: i) robust feature extraction from raw time-intensity curves, ii) voxel segmentation, and iii) voxel classification based on a learning-by-example approach. In the first step, few robust features that compactly represent the response of the tissue to the DCE-MRI analysis are computed. The second step provides a segmentation based on the mean shift (MS) paradigm, which has recently shown to be robust and useful for different and heterogeneous clustering tasks. Finally, in the third step, a support vector machine (SVM) is trained to classify voxels according to the labels obtained by the clustering phase (i.e., each class corresponds to a cluster). Indeed, the SVM is able to classify new unseen subjects with the same kind of tumor. Results: Experiments on different subjects affected by the same kind of tumor evidence that the extracted regions by both the MS clustering and the SVM classifier exhibit a precise medical meaning, as carefully validated by the medical researchers. Moreover, our approach is more stable and robust than methods based on quantification of DCE-MRI data by means of pharmacokinetic models. Conclusions: The proposed method allows to analyze the DCE-MRI data more precisely and faster than previous automated or manual approaches.

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Eveno, Clarisse, Aminata Haidara, Ibrahim Ali, Cynthia Pimpie, Massoud Mirshahi und Marc Pocard. „Experimental pharmacokinetics evaluation of chemotherapy delivery by PIPAC for colon cancer: first evidence for efficacy“. Pleura and Peritoneum 2, Nr. 2 (27.06.2017): 103–9. http://dx.doi.org/10.1515/pp-2017-0015.

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AbstractBackgroundPressurised intraperitoneal aerosol chemotherapy (PIPAC) is a novel technique of intraperitoneal chemotherapy devoted to unresectable peritoneal metastasis (PM). The first results obtained with PIPAC in preclinical models of colon cancer are presented here.MethodsIn vitro, PIPAC (normotherm oxaliplatin at 0.028 mg/mL for 10 min at 1.6 bars) and HIPEC (hyperthermic oxaliplatin at 0.14 mg/mL for 30 min) were compared using the apoptosis and proliferation assay on two colon cancer cell lines (LS 174 and CT 26); ex vivo tumours from an orthotopic mouse model of PM and non-tumour peritoneum from a patient treated according to the two modalities were assessed, investigating the percentage of penetration of oxaliplatin in the tumour and oxaliplatin concentration below the peritoneum. In vivo, a mouse model of colon (CT 26) PM was used to create a PIPAC model (same modalities) for the comparison of IV oxaliplatin (at 5 mg/mL).ResultsIn vitro, the rate of apoptotic and proliferative cells as well as the level of oxaliplatin penetration in tumour nodes was higher in PIPAC groups with less systemic passage through the peritoneum. In vivo, in the colon PM mouse model, the peritoneal cancer index (PCI) was decreased to the same level using PIPAC or IV oxaliplatin. Systemic passage was lower in the PIPAC group.ConclusionsPIPAC with low-dose oxaliplatin is efficient in both in vitro and in vivo models of colon PM. Lower concentrations of chemotherapy are needed in PIPAC to achieve the same effect as IV chemotherapy on PCI. With a very low systemic oxaliplatin passage, this technique of drug delivery seems to be as effective as IV delivery for PM control.

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Moreno, Ofir M., Vanessa Zann und Pui Leung. „Clinical Pharmacokinetics and Pharmacodynamics of Pwt-143, an Oral, Potent and Selective Inhibitor of Phosphatidylinositol 3-Kinase P110delta, Following Single Oral Administration to Healthy Volunteers“. Blood 126, Nr. 23 (03.12.2015): 4858. http://dx.doi.org/10.1182/blood.v126.23.4858.4858.

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Abstract Background: The Phosphatidylinositol 3-Kinases p110δ isoform (P110δ PI3K) is hyperactive in B cell malignancies and is central to multiple signaling pathways that drive proliferation, survival, homing and retention of malignant cells in lymphoid tissue and bone marrow. PI3Kd inhibitors have demonstrated important clinical activity in various lymphoid malignancies, albeit with certain toxicities and PK limitations. PWT-143, comprised of a novel molecular scaffold that is distinctive from other known PI3Kd-selective inhibitors, is a potent and selective inhibitor of P110δ PI3K enzymatic activity. PWT-143 exhibits low nanomolar potency in cellular assays, as well as in a pre-clinical whole blood functional assay of basophil activity (poster presented at 54th ASH Annual Meeting, 2012). PWT-143 also demonstrated highly favorable pharmacokinetics from oral administration in preclinical experiments. Preclinical toxicology and safety pharmacology data supported initial clinical assessment of oral PWT-143 in healthy volunteers, consistent with its target selectivity profile. Here we report the initial PK and PD results of a single dose of oral PWT-143 in healthy volunteers. Methods: A flexible, adaptive first-in-human study was conducted using a Translational Pharmaceutics® platform which enables rapid real-time PK/PD analysis and GMP manufacture of drug products between dosing periods. Based on the NOAEL in rats and dogs, with a standard safety margin for a first-in-human study, the starting dose level was 10 mg, with higher doses and/or formulation adjustments to be selected, based on review of emerging safety, tolerability and pharmacokinetic data. Blood samples were collected at regular time intervals, and plasma concentrations of PWT-143 were measured using a validated liquid chromatography tandem mass spectrometry method. Blood samples were also collected for testing with a PD assay; specifically, basophil activation assessed via CD63 expression by flow cytometry following ex-vivo stimulation with an anti-FCeR1 monoclonal antibody. Results: To date, subjects (n=3/cohort) have been orally administered 10 mg and 30 mg of PWT-143, and escalation is continuing (n=6/cohort). The 10 mg and 30 mg doses resulted in up to 55 % and 80 % inhibition of basophil activation, respectively, within 4 hours of dosing. Both doses resulted in no reported Adverse Events nor clinically significant changes in vital signs, ECGs or safety laboratory assessments. The geometric mean Cmax and half-life were 3.9 ng/ml (range; 2.0-6.6 ng/ml) and 29 hours (range; 20-42 hours), respectively, following oral administration of 30 mg. Conclusions: Measurable plasma levels of PWT-143, as well as significant inhibition of basophil activation have been observed at the lowest planned dose levels. These findings suggest that PWT-143 is orally bioavailable and exhibits potent on-target activity in humans. PK results suggest daily dosing is achievable. Results from the completed study with all dose levels will be presented. Disclosures No relevant conflicts of interest to declare.

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Ferreira, Guilherme S., Désirée H. Veening-Griffioen, Wouter P. C. Boon, Ellen H. M. Moors und Peter J. K. van Meer. „Levelling the Translational Gap for Animal to Human Efficacy Data“. Animals 10, Nr. 7 (15.07.2020): 1199. http://dx.doi.org/10.3390/ani10071199.

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Reports of a reproducibility crisis combined with a high attrition rate in the pharmaceutical industry have put animal research increasingly under scrutiny in the past decade. Many researchers and the general public now question whether there is still a justification for conducting animal studies. While criticism of the current modus operandi in preclinical research is certainly warranted, the data on which these discussions are based are often unreliable. Several initiatives to address the internal validity and reporting quality of animal studies (e.g., Animals in Research: Reporting In Vivo Experiments (ARRIVE) and Planning Research and Experimental Procedures on Animals: Recommendations for Excellence (PREPARE) guidelines) have been introduced but seldom implemented. As for external validity, progress has been virtually absent. Nonetheless, the selection of optimal animal models of disease may prevent the conducting of clinical trials, based on unreliable preclinical data. Here, we discuss three contributions to tackle the evaluation of the predictive value of animal models of disease themselves. First, we developed the Framework to Identify Models of Disease (FIMD), the first step to standardise the assessment, validation and comparison of disease models. FIMD allows the identification of which aspects of the human disease are replicated in the animals, facilitating the selection of disease models more likely to predict human response. Second, we show an example of how systematic reviews and meta-analyses can provide another strategy to discriminate between disease models quantitatively. Third, we explore whether external validity is a factor in animal model selection in the Investigator’s Brochure (IB), and we use the IB-derisk tool to integrate preclinical pharmacokinetic and pharmacodynamic data in early clinical development. Through these contributions, we show how we can address external validity to evaluate the translatability and scientific value of animal models in drug development. However, while these methods have potential, it is the extent of their adoption by the scientific community that will define their impact. By promoting and adopting high quality study design and reporting, as well as a thorough assessment of the translatability of drug efficacy of animal models of disease, we will have robust data to challenge and improve the current animal research paradigm.

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Le, Kha, Marvin Cohen, Yue Chen, Hyeryun Kim, Bruce Silver, Sam Agresta, Elizabeth Merica et al. „Population Pharmacokinetics and Pharmacodynamics of AG-348 in Healthy Human Volunteers Guide Dose Selection for the Treatment of Pyruvate Kinase Deficiency“. Blood 126, Nr. 23 (03.12.2015): 3336. http://dx.doi.org/10.1182/blood.v126.23.3336.3336.

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Abstract INTRODUCTION: Pyruvate kinase (PK) deficiency is a glycolytic enzymopathy that results in non-spherocytic hemolytic anemia with a variable clinical presentation, ranging from mild or fully compensated forms to life-threatening neonatal anemia and life-long chronic hemolytic anemia associated with severe, debilitating co-morbidities. PK deficiency is caused by mutations in the PKLR gene, which in the red blood cell (RBC) results in defective pyruvate kinase isoform R (PK-R). PK-R catalyzes the final, irreversible step in glycolysis, the process on which mature RBCs rely almost exclusively to generate the energy carrier molecule adenosine triphosphate (ATP). PK-deficient RBCs and their progenitors are characterized by changes in metabolism associated with defective glycolysis, including a build-up of phosphoenolpyruvate (PEP) and 2,3-diphosphoglycerate (2,3-DPG), and lowered ATP levels. AG-348 is an orally available, allosteric activator of PK-R. It is hypothesized that intervention with AG-348 restores glycolytic pathway activity and normalizes RBC metabolism in vivo (Kung C et al. Blood, 2013). Biochemical experiments demonstrate that AG-348 is a potent pan-activator of many PK-R alleles associated with PK deficiency. Treatment of PK-deficient patient RBCs ex vivo with AG-348 results in increased ATP levels, and reductions in PEP and 2,3-DPG, consistent with pharmacological activation of the PK-R enzyme. This analysis integrates the pharmacokinetic and pharmacodynamic (PK/PD) properties of AG-348 in healthy human volunteers using population PK/PD modeling and simulation. METHODS: PK/PD modeling using a non-linear mixed effects approach was performed to understand the pharmacokinetics of AG-348 and PK/PD relationship of AG-348 to 2,3-DPG and ATP in humans. The PK/PD model integrated data from two phase 1, single-center, randomized, double-blind, placebo-controlled, dose escalation studies (one single and one 14-day multiple ascending dose) that enrolled a total of 96 healthy volunteers (Yang H et al. EHA Learning Center, 2015). AG-348 dose level ranged from 15-2500 mg given once (QD) or twice (BID) daily. Blood was collected from all patients to assess AG-348 pharmacokinetics, and for determination of levels of ATP and 2,3-DPG. Population simulations using the final model were performed to examine the dose-exposure-biomarkers relationship at various dose levels and duration of dosing. RESULTS: AG-348 showed rapid absorption following oral administration. Plasma exposure of AG-348 increased in a dose-proportional manner following a single dose. A three-compartmental model with a non-linear absorption compartment and a saturable induced enzyme compartment best described the pharmacokinetics of AG-348. Time-varying clearance was added to describe the observed decrease in exposure over time with multiple dosing; this is consistent with pre-clinical data that AG-348 is a moderate inducer of CYP3A4, the major oxidation pathway of AG-348. The multiple-dose data were well described by a semi-mechanistic autoinduction model with an indirect model and a saturable induction compartment. The PK/PD relationship between plasma AG-348 to ATP and 2,3-DPG showed best fit with a turnover model where the drug effect was described by an Emax model. Model simulations predicted maximum enzyme induction and PD response 3 weeks after the first dose following BID dosing. Population PK/PD simulations further supported the choice of 50 mg and 300 mg BID doses for the phase 2 study (Fig 1 and 2). The proposed current model incorporating PK/PD data over a wide range of AG-348 exposures and time-varying changes in clearance provides a useful tool for prediction of AG-348 pharmacokinetics that can be used to optimize AG-348 dosing for PK deficiency treatment. Furthermore, the population PK/PD model of AG-348 to ATP and 2,3-DPG biomarkers in healthy volunteers provides a good foundation to facilitate the analysis and understanding of patient data in the ongoing phase 2 study. CONCLUSION: This study represents the first comprehensive longitudinal analysis of AG-348 and its PD activity in humans. This integrated PK/PD model, incorporating time-varying PK/PD properties, forms the basis for understanding the exposure-response relationship in the ongoing phase 2 and future clinical studies of AG-348, as well as providing guidance on dosing selection to optimize the treatment of PK deficiency. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Le: Agios Pharmceuticals: Employment, Equity Ownership. Cohen:Agios: Consultancy. Chen:Agios: Employment. Kim:Agios: Employment. Silver:Agios: Consultancy. Agresta:Agios: Employment, Equity Ownership. Merica:Agios Pharmaceuticals: Employment, Equity Ownership. Kung:Agios: Employment, Equity Ownership. Kosinski:Agios: Employment, Equity Ownership; General Electric: Equity Ownership; SDIX: Equity Ownership. Silverman:Agios: Employment, Equity Ownership. Biller:Agios Pharmaceuticals: Employment, Equity Ownership; Arbutus BioPharma (formerly Tekmira): Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Syros Pharmaceuticals: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Arvinas: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Denali: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Yang:Agios Pharmaceuticals: Employment, Equity Ownership.

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Tomirotti, Andrea, Giuseppe Merlino, Alessio Fiascarelli, Simone Baldini, Alessia Tagliavini, Elisa Borella, Milena Mazan et al. „Identification of a Pharmacodynamic Biomarker for SEL24/MEN1703, a First-in-Class Dual PIM/FLT3 Kinase Inhibitor for Acute Myeloid Leukemia, and Its Implementation in the First-in-Human Study CLI24-001“. Blood 134, Supplement_1 (13.11.2019): 5087. http://dx.doi.org/10.1182/blood-2019-124800.

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SEL24/MEN1703 is a first-in-class, orally available, dual PIM/FLT3 kinase inhibitor currently investigated in patients with Acute Myeloid Leukemia (AML) in the first-in-human study CLI24-001 (NCT03008187). PIM and FLT3 kinases are considered to play an important role in AML and are inhibited by SEL24/MEN1703. Moreover, there is evidence that inhibition of PIM kinases might contribute to overcoming acquired resistance induced by approved FLT3 inhibitors1. In AML, different signal transducers in the FLT3 pathway are substrates of kinases. Therefore, their phosphorylation levels might be modulated by kinase inhibitors and may be exploited as a potential pharmacodynamic biomarker in clinical development. In particular, phosphorylation of S6, 4E-BP1, and STAT5 is regulated by both FLT3 and PIM1/2. Thus, the objective of this investigation was to identify the most promising pharmacodynamic biomarker/s for implementation in the clinical trials of SEL24/MEN1703. Initially, we assessed the in vitro cytotoxic effect of SEL24/MEN1703 in a panel of 26 AML cell lines harboring different genetic mutations, to identify suitable cell lines for subsequent experiments. In the selected panel of AML cell lines, SEL24/MEN1703 resulted in the inhibition of phosphorylation of S6, 4-EBP1 and STAT5 as measured by immunoblotting. Notably, the reduction in phosphorylated S6 (pS6) in response to SEL24/MEN1703 was particularly evident. Since SEL24/MEN1703 displays a broad cytotoxic activity in AML cell lines, we clustered sensitive and resistant cell lines considering 0.5 μM as the IC50 cut-off value. Then, we investigated the relationship between SEL24/MEN1703 cytotoxic activity in AML cell lines and the inhibition of the above mentioned phosphorylated proteins in a 24-hour cytotoxic assay, showing a correlation between IC50 and the reduction of pS6 (Pearson correlation coefficient: -0.6905, R2= 0.477). To further confirm the in vitro data, SEL24/MEN1703 ability to modulate phosphoproteins was assessed also in xenograft mice bearing MOLM-16 cell line. The phosphorylation status of S6, 4E-BP1 and STAT5 was analyzed by immunoblot in tumor tissues from mice treated at 25 mg/kg of SEL24/MEN1703 at baseline and at 4, 8, and 16 hours after treatment. Results showed that also in vivo, SEL24/MEN1703 administration resulted in a decrease of pS6, with maximum reduction in this parameter observed 4 hours after the administration of the investigational compound. Based on these results, pS6 was identified as the pharmacodynamic biomarker to be implemented in the CLI24-001 clinical trial. Among different available methods, flow cytometry was selected as the preferred platform to analyze patient samples, because of its ability to provide quantitative assessment of cellular events and pharmacodynamic evaluation in a selected, relevant cell subpopulation, such as the AML blast cells. The assessment of pS6 in the clinical trial is planned both at baseline and at cycle 1 day 14 for whole blood and bone marrow. In addition, pS6 levels will be measured in whole blood at additional time points during treatment cycles. We have implemented the measurement of pS6 in the CLI24-001 trial, and pS6 levels as well as their relationship with the main pharmacokinetic parameters in patients treated with SEL24/MEN703 at 100 and 125 mg will be presented. 1Green A.S. et al., Pim kinases modulate resistance to FLT3 tyrosine kinase inhibitors in FLT3-ITD acute myeloid leukemia, Sci Adv, 2015 Disclosures Tomirotti: Menarini Ricerche S.p.A.: Employment. Merlino:Menarini Ricerche S.p.A.: Employment. Fiascarelli:Menarini Ricerche S.p.A.: Employment. Baldini:Menarini Ricerche S.p.A.: Employment. Tagliavini:Menarini Ricerche S.p.A: Employment. Borella:Menarini Ricerche S.p.A.: Employment. Mazan:Selvita S.A.: Employment. Brzózka:Selvita S.A.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Bressan:Menarini Ricerche S.p.A.: Employment. Pellacani:Menarini Ricerche S.p.A.: Employment; Amgen: Equity Ownership. Salerno:Menarini Ricerche S.p.A.: Employment. Binaschi:Menarini Ricerche S.p.A.: Employment. Bellarosa:Menarini Ricerche S.p.A.: Employment.

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Mohell, Nina, Charlotta Liljebris, Jessica Alfredsson, Ylva Lindman, Maria Uustalu, Thomas Uhlin, Mats R. H. Linderholm und Klas G. Wiman. „Preclinical Efficacy and Toxicology Studies of APR-246, a Novel Anticancer Compound Currently In Clinical Trials for Refractory Hematological Malignancies and Prostate Cancer“. Blood 116, Nr. 21 (19.11.2010): 1806. http://dx.doi.org/10.1182/blood.v116.21.1806.1806.

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Abstract Abstract 1806 The tumor suppressor protein p53 is a transcription factor involved in cell cycle arrest, senescence and apoptosis. The p53 gene is frequently mutated in cancer, and cancer cells carrying defects in p53 are generally more resistant to conventional chemotherapy. Thus, restoration of wild type function of p53 is a promising novel strategy for cancer therapy. APR-246 belongs to a new class of small molecules (quinuclidinones) that reactivates non-functional p53 by promoting its correct folding and triggering apoptosis (Lambert et al. Cancer Cell 15, 2009). The lead compound of APR-246, PRIMA-1 (p53 Reactivation and Induction of Massive Apoptosis) was identified by a cellular screen of a NCI (National Cancer Institute) library, and an optimization program led to the discovery of the analog APR-246 (PRIMA-1MET). In various in vitro,ex vivo andin vivo cancer models, APR-246 has shown good antitumor activity. It reduces cell viability and/or induces apoptosis in a large number of human cancer cell lines with different p53 status, including leukemia, lymphoma and myeloma cell lines (Mohell et al. Blood 114, 2009). Ex vivo efficacy of APR-246 alone and in combination with conventional chemotherapeutic drugs has been shown in primary cells from patients with acute myeloid leukemia (AML) (Jonsson-Videsater et al. Blood 114, 2009). Ex vivo efficacy of APR-246 has also been shown in primary cells from patients with chronic lymphocytic leukemia (CLL). APR-246 was 4–8 fold more potent in killing malignant than normal lymphocytes, whereas common cytostatics often have negative ratio (Mohell et al. Blood 114, 2009). In vivo efficacy of APR-246/PRIMA-1 has been demonstrated in xenograft studies using many solid tumor cell lines (Mohell et al. Blood 114, 2009). Here we present results from studies with APR-246 using in vivo systemic and metastasic xenograft model with the human AML primary cell line AML-PS. This model was established by Giovazzi et al. (Int. J. Cancer 61, 1995) and is considered as a predictive in vivo model for human AML. In addition, some key results from preclinical safety and toxicology studies are reported. Briefly, SCID (severe combined immunodeficiency) mice were inoculated i.v. with 5×106 human AML-PS primary cells. Three days after inoculation treatment with i.v. injections of APR-246 (200 and 300 mg/kg), twice daily for 10 days, was initiated. Mice were monitored daily for health status and mortality. Blood samples were collected for determination of the percentage of circulating human leukemia cells by FACS analysis. Human leukemic cells were detected using a fluorescent antibody against the major histocompatibility complex (HLA). In parallel, pharmacokinetic experiments to measure the concentration of APR-246 in the blood were performed. We found that APR-246 had a statistically significant antitumor effect by decreasing the percentage of circulating human AML-PS cells and increasing the survival time of the mice (P=0.0024, n=10). A good correlation between increase in survival time and decrease in circulating tumor cells in the blood was observed. Further in vivo efficacy studies using various treatment schedules and combinations with conventional cytostatics are ongoing. APR-246 was also investigated in pivotal toxicology studies using single and repeat-dose regimen. In dogs, APR-246 was well tolerated when administered as 2 h infusion with NOAEL (no observed adverse effect level) of 200 mg/kg/day (4000 mg/m2/day). In both dogs and mice, Cmax levels less than 100 μg/ml did not induce any toxicity, regardless of the administration protocol. No systemic target organ toxicity was observed in mice or dogs, including blood and bone-marrow parameters. In conclusion, APR-246 has in various efficacy models demonstrated significant antitumor activity and a unique pharmacological profile. In preclinical safety/toxicity studies no toxicity at predicted therapeutic plasma concentrations was observed. Thus, APR-246 appears to be a promising novel anticancer compound to treat patients resistant to common chemotherapy. Currently, APR-246 is investigated in a dose escalating Phase I/IIa First-in-Man study for refractory hematological malignancies and prostate cancer. The Phase II Proof of Concept study is planned to start in 2011. Disclosures: Mohell: Aprea AB: Employment. Liljebris:Aprea AB: Employment. Alfredsson:Aprea AB: Employment. Lindman:Aprea AB: Employment. Uustalu:Aprea AB: Employment. Uhlin:Aprea AB: Employment. Linderholm:Aprea AB: Consultancy. Wiman:Aprea AB: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

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Zhu, Zhihong, Hao Pan, Yuenan Li und Weisan Pan. „Evaluation of the Synergism Mechanism of Tamoxifen and Docetaxel by Nanoparticles“. Anti-Cancer Agents in Medicinal Chemistry 19, Nr. 16 (23.01.2020): 1991–2000. http://dx.doi.org/10.2174/1871520619666190702120829.

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Background: Our previous studies have shown that Docetaxel (DTX) and Tamoxifen (TMX) loaded nanoparticles(Co-NPs) could exhibit a synergistic effect on estrogen receptor positive cell lines. In the current study，we have studied the synergistic effect of Co-NPs and underlying possible molecular mechanism. Methods: Cell apoptosis assay, pharmacokinetic experiment and immunohistochemistry experiment were used to explore the synergistic effect and underlying possible mechanism in vitro and in vivo. Results: Cell apoptosis assay revealed that Co-NPs could mediate cell sensitization to a cytotoxic agent, resulting in remarkable cell apoptosis. In addition, pharmacokinetic experiment research showed that Co-NPs have longer circulation time in vivo, which could prolong the treatment time of the chemotherapeutic drugs. Immunohistochemistry experiment revealed that the Co-NPs could downregulate the expression of P-gp level to reduce the drugs’ efflux. Conclusion: The possible mechanism of the synergistic effect of DTX and TMX by Co-NPs was attributed to the longer in vivo circulation time, significantly increased rate of cell apoptosis and downregulated expression of P-gp level to the tumor cells.

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Benlhassan-Chahour, Kadija, Claude Penit, Vincent Dioszeghy, Florence Vasseur, Geneviève Janvier, Yves Rivière, Nathalie Dereuddre-Bosquet, Dominique Dormont, Roger Le Grand und Bruno Vaslin. „Kinetics of Lymphocyte Proliferation during Primary Immune Response in Macaques Infected with Pathogenic Simian Immunodeficiency Virus SIVmac251: Preliminary Report of the Effect of Early Antiviral Therapy“. Journal of Virology 77, Nr. 23 (01.12.2003): 12479–93. http://dx.doi.org/10.1128/jvi.77.23.12479-12493.2003.

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ABSTRACT The aim of this study was to evaluate the kinetics of lymphocyte proliferation during primary infection of macaques with pathogenic simian immunodeficiency virus (SIV) and to study the impact of short-term postexposure highly active antiretroviral therapy (HAART) prophylaxis. Twelve macaques were infected by intravenous route with SIVmac251 and given treatment for 28 days starting 4 h postexposure. Group 1 received a placebo, and groups 2 and 3 received combinations of zidovudine (AZT), lamivudine (3TC), and indinavir. Macaques in group 2 received AZT (4.5 mg/kg of body weight), 3TC (2.5 mg/kg), and indinavir (20 mg/kg) twice per day by the oral route whereas macaques in group 3 were given AZT (4.5 mg/kg) and 3TC (2.5 mg/kg) subcutaneously twice per day, to improve the pharmacokinetic action of these drugs, and a higher dose of indinavir (60 mg/kg). The kinetics of lymphocyte proliferation were analyzed by monitoring 5-bromo-2′-deoxyuridine (BrdU) uptake ex vivo and by fluorescence-activated cell sorting analysis. HAART did not protect against SIV infection but did strongly impact on virus loads: viremia was delayed and lowered during antiviral therapy in group 2, with better control after treatment was stopped, and in group 3, viremia was maintained at lower levels during treatment, with virus even undetectable in the blood of some macaques, but there was no evidence of improved control of the virus after treatment. We provide direct evidence that dividing NK cells are detected earlier than dividing T cells in the blood (mostly in CD45RA− T cells), mirroring plasma viremia. Dividing CD8+ T cells were detected earlier than dividing CD4+ T cells, and the highest percentages of proliferating T cells coincided with the first evidence of partial control of peak viremia and with an increase in the percentage of circulating gamma interferon-positive CD8+ T cells. The level of cell proliferation in the blood during SIV primary infection was clearly associated with viral replication levels because the inhibition of viral replication by postexposure HAART strongly reduced lymphocyte proliferation. The results and conclusions in this study are based on experiments in a small numbers of animals and are thus preliminary.

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Corman, Hannah N., Douglas A. Shoue, Bruce J. Melancon und Mary Ann McDowell. „52500 Characterization of a Series of 1,4-diaryl-pyrazolo-pyridinones as Anti-Leishmanial Agents“. Journal of Clinical and Translational Science 5, s1 (März 2021): 3. http://dx.doi.org/10.1017/cts.2021.409.

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ABSTRACT IMPACT: The first-line chemotherapies used to treat leishmaniasis are highly toxic intravenous antimonials yet drug resistance has begun to develop, causing the use of oral treatment options with high price tags; there is a strong need for new, safe, and effective chemotherapeutic agents to treat leishmaniasis. OBJECTIVES/GOALS: This study was conducted in order to identify novel chemical compounds that exhibit anti-leishmanial activity and to further characterize their efficacy and toxicity in in vitro and in vivo systems in the hopes of future chemotherapeutic developments. METHODS/STUDY POPULATION: A total of 28 unique 1,4-diaryl-pyrazolo-pyridinone (1,4-DAPP) compounds were synthesized and anti-leishmanial efficacy and host cell toxicity were determined using L. donovani mCherry-expressing amastigotes and THP-1 macrophages. Additional pharmacokinetic analyses of a potent 1,4-DAPP compound were conducted, revealing a potential metabolite structure. A select group of the novel compounds were screened in a cutaneous leishmaniasis (CL) murine model using L. major mCherry-expressing parasites and female Balb/C mice. The treatment consisted of 10 intralesional injections of compound over a period of 4 weeks, while lesion growth was monitored via fluorescence and manual measurements. RESULTS/ANTICIPATED RESULTS: Four experimental compounds had IC50 values less than 5 micromolar, providing similar anti-leishmanial activity to Miltefosine. Compound 9279817 had a clearance almost twice the rate of normal hepatic blood flow and had a relatively high volumes of distribution, indicating this compound is rapidly cleared and distributes into tissues. In vitro rat liver microsome assays suggest a rapid metabolism of 9279817 and MS/MS results suggest this metabolite is most likely formed via oxidation of the sulfur on the lower aryl ring. This sulfoxide metabolite has similar efficacy as the parent compound and does not exhibit toxicity in vitro. Three of the experimental compounds behaved similarly to the antimony positive control in the murine CL model. DISCUSSION/SIGNIFICANCE OF FINDINGS: This study revealed a novel structural class of compounds that have anti-leishmanial activity. Experiments show compounds with similar efficacy to Miltefosine while having significantly less cytotoxicity, suggesting that the 1,4-DAPP structural class could be further developed as a potential chemotherapeutic.

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Peterson, Peter, Katherine K. Soh, Ye Sol Lee, Wontak Kim, Clifford J. Whatcott, Adam Siddiqui-Jain, David J. Bearss und Steven L. Warner. „ALK2 Inhibition Via TP-0184 Abrogates Inflammation-Induced Hepcidin Expression and Is a Potential Therapeutic for Anemia of Chronic Disease“. Blood 126, Nr. 23 (03.12.2015): 273. http://dx.doi.org/10.1182/blood.v126.23.273.273.

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Abstract Hepcidin, a key liver peptide hormone, is essential to the regulation of bioavailable iron and erythropoiesis. Activin-like kinase receptor 2 (ALK2) signaling, via SMAD transcription factors, plays an important part in the regulation of hepcidin expression induced by pro-inflammatory cytokines. In chronic inflammatory conditions, such as rheumatoid arthritis, chronic kidney disease, colitis, and in some forms of cancer, hepcidin expression is induced. This induction of hepcidin expression results in lower levels of bioavailable iron, ultimately leading to the onset of anemia. Hepcidin regulates bioavailable iron levels by binding to and inhibiting the cellular iron pump, ferroportin. Ferroportin is important to macrophage-based iron recycling and dietary iron absorption. Several reports have suggested that lowering hepcidin provides a novel approach for targeting the clinical challenge of anemia. Currently approved approaches for these patients rely on transfusions and the use of erythropoietin-based therapies. Unfortunately, neither of these approaches address the underlying chronic inflammation or hepcidin induction and resulting anemia. In this report, we validate our small molecule inhibitor of ALK2, TP-0184, for the treatment of hepcidin-driven anemia of chronic diseases. Biochemical assays demonstrate that TP-0184 inhibits of the kinase activity of ALK2 with an IC50 of 5 nM. In vitro, TP-0184 is effective at targeting hepcidin expression with an EC50 lower than 100 nM in HepG2 cells. Three in vivo models were also explored for our validation of TP-0184. In our first study, turpentine oil TO was injected into the intrascapular fat pad of C57BL/6 mice to induce an acute inflammatory response that results in hepcidin-driven anemia. The animals were dosed with TP-0184 1 hour prior to TO treatment and once again 8 hours later. The TO-mediated acute inflammatory response in mice resulted in a 14-fold increase in liver hepcidin levels. Two oral doses of TP-0184 at 100 mg/kg, separated by 8 hours, reversed the induction of hepcidin that followed TO treatment. TP-0184 was tested at multiple doses in which efficacy was observed. In our second in vivo model, we induced anemia via intraperitoneal injection with heat-inactivated Brucella abortus. The mice were treated daily with TP-0184 for 3-7 days, after which, whole blood, plasma and livers were collected, from which liver and plasma hepcidin, plasma iron, and complete blood counts were assessed. Treatment with 100 mg/kg TP-0184 completely abrogated the Brucella abortus-induced reduction of hemoglobin and total red blood cell counts. In our third in vivo study, TP-0184 was also evaluated in the TC-1 lung cancer model for cancer-induced anemia. TC-1 tumor-bearing animals exhibited a 3-fold increase in liver hepcidin levels, which was reversed by dosing with 25 mg/kg TP-0184. From these experiments, we conclude that TP-0184 is a potent and selective inhibitor of ALK2 with demonstrated activity in multiple preclinical models of anemia associated with inflammation. TP-0184 also demonstrates favorable pharmacokinetic properties as well as good drug-like qualities, making it a strong candidate molecule with which to move into IND-enabling studies and formal clinical development. The current study supports a clinical development approach focused on anemia of chronic disease where an erythropoietin-sparing approach might offer significant clinical benefit to patients. Disclosures Peterson: Tolero Pharmaceuticals: Employment. Soh:Tolero Pharmaceuticals: Employment. Lee:Tolero Pharmaceuticals: Employment. Kim:Tolero Pharmaceuticals: Employment. Whatcott:Tolero Pharmaceuticals: Employment. Siddiqui-Jain:Tolero Pharmaceuticals: Employment. Bearss:Tolero Pharmaceuticals: Employment. Warner:Tolero Pharmaceuticals: Employment.

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Kopacz, Dan J., und Christopher M. Bernards. „Effect of Clonidine on Lidocaine Clearance In Vivo“. Anesthesiology 95, Nr. 6 (01.12.2001): 1371–76. http://dx.doi.org/10.1097/00000542-200112000-00015.

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Background The addition of clonidine to local anesthetics has been shown to prolong both peripheral and central neuraxial local anesthetic blocks. Whether clonidine prolongs local anesthetic block by a pharmacokinetic effect or a pharmacodynamic effect is unclear. By directly measuring lidocaine tissue concentrations at the site of injection in the presence and absence of clonidine, this study was designed to address this question. Methods Microdialysis probes were placed adjacent to the superficial peroneal nerve in both feet of seven volunteers. Plain lidocaine (1%) was injected along one nerve, and lidocaine with clonidine (10 microg/ml) was injected along the other nerve in a double-blind, randomized manner. The extracellular fluid was then sampled for lidocaine concentration at 5-min intervals using microdialysis, cutaneous blood flow was assessed by laser Doppler at 10-min intervals, and sensory block was assessed every 10 min until resolution. Results Consistent with previous studies, clonidine prolonged lidocaine sensory block. Blood flow increased in both groups but was significantly lower in the clonidine group, especially during the first 60 min. Consistent with the lower blood flow, the area under the lidocaine concentration-versus-time curve was significantly greater in the clonidine group during the first 60 min. Conclusion When added to lidocaine, clonidine prolonged peripheral nerve block. The pharmacokinetic data suggest that the mechanism of prolongation is at least in part pharmacokinetic.

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Tang, Zhongyao, Yuanyuan Hou, Xueyan Hu, Aina Liu, Leefong Yau, Tiantian Tong, Zhihong Jiang und Gang Bai. „Metabolite identification and pharmacokinetic study of platycodi radix (Jiegeng) in vivo“. RSC Advances 7, Nr. 59 (2017): 37459–66. http://dx.doi.org/10.1039/c7ra04814a.

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Liu, Guoqiang, Leilei Dong, Kuan Lu, Sisi Liu und Yingying Zheng. „Preparation and In Vivo Pharmacokinetics of the Tongshu Suppository“. BioMed Research International 2016 (2016): 1–5. http://dx.doi.org/10.1155/2016/1691579.

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Astragalus polysaccharide (APS) (used for intestinal protection) was added to formulate the Tongshu suppository to improve the pharmacokinetics of Aceclofenac, which were assessed in New Zealand rabbits using an orthogonal experimental design. The single-agent Aceclofenac was taken as the control formulation. The concentration-time and drug release curves were drawn, andTmax(min),Cmax(μg·mL−1),AUC0→∞, and MRT were compared using a pharmacokinetic systems program. The formulated Tongshu suppository had moderate hardness, a smooth surface with uniform color, and theoretical drug-loading rate of 8%. Its release rate was in accordance with the drug preparation requirements. The concentration-time curves and drug release curves revealed that the maximum concentrations (Cmax) were4.18±1.03 μg·mL−1and3.34±0.41 μg·mL−1for the Tongshu and Aceclofenac suppositories, respectively, showing statistically insignificant difference, while the peak times were34.87±4.69 min and34.76±6.34 min, respectively, also showing statistically insignificant difference. Compared with the Aceclofenac suppository, the relative bioavailability of the Tongshu suppository was 104.4%, and the difference between them was statistically insignificant. In this experiment, the Tongshu suppository was prepared using the hot-melt method. In vivo pharmacokinetic studies confirmed it had higher bioavailability than the Aceclofenac suppository.

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Samtsov, M. P., D. S. Tarasov, A. Р. Lugovski, Р. Т. Petrov, A. О. Savin, R. D. Zilberman und E. S. Voropay. „Spectral properties of indotricarbocyanine dye in tissues of experimental animals“. Doklady BGUIR 18, Nr. 8 (27.12.2020): 5–13. http://dx.doi.org/10.35596/1729-7648-2020-18-8-5-13.

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The paper presents the results of studies of the spectral properties of a photosensitizer based on indotricarbocyanine dye when accumulating in tissues of experimental animals. Using laser fluorescence spectroscopy, the in vivo and ex vivo fluorescence spectra of tissue-localized indotricarbocyanine dye were obtained for different time counts after intravenous administration. The profile of the pharmacokinetics of its accumulation and withdrawal was determined from the change in the intensity of fluorescence in the tumor and healthy muscle tissues of the photosensitizer. A monotonic deformation of its fluorescence spectrum was revealed in the tissues of tumor nodes and muscles of the thigh when registered through the skin over time after intravenous administration. The achievement of the maximum accumulation of the photosensitizer in the tumor correlates with the stabilization of the shape of its in vivo fluorescence spectrum. Thus, the maximum shift can be used as a diagnostic indicator of the maximum accumulation of indotricarbocyanine photosensitizer in the tumor tissues. The results were confirmed for two groups of animals: the first one – black mice of the C57Bl/6 line with an inoculated tumor of Clone M3 melanoma, the second – white mice of the ICR line with an inoculated tumor of Ehrlich ascites carcinoma. The analysis of the shape of the fluorescence spectrum of the photosensitizer during registration through the skin for animals with different colors has been carried out.

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Heaton, William L., Anna M. Eiring, Nadeem A. Vellore, Diana Resetca, Sina Haftchenary, David Rosa, Ahmed M. Ali et al. „Design, Optimization, and Pre-Clinical Evaluation of Direct, Mechanism-Based STAT3 Inhibitors for Treating Myeloid Disorders“. Blood 124, Nr. 21 (06.12.2014): 4816. http://dx.doi.org/10.1182/blood.v124.21.4816.4816.

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Abstract We have identified STAT3 as a convergence point for oncogenic signaling in tyrosine kinase inhibitor (TKI)-resistant chronic myeloid leukemia (CML) lacking BCR-ABL1 kinase domain mutations. In addition, we found that STAT3 activity contributes to disease in other myeloid disorders, including acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs). Utilizing TKI-resistant CML as a model system, we identified BP-5-087 as a small molecule inhibitor of STAT3 that reduces STAT3 phosphorylation and nuclear transactivation (Eiring et al. Leukemia, 2014). Binding of BP-5-087 to the STAT3 SH2 domain was initially assessed using fluorescence polarization (FP) assays and high-resolution computational docking simulations. To further validate the binding motif of BP-5-087, we conducted time-resolved electrospray ionization mass spectrometry/hydrogen-deuterium exchange experiments. Fold-change in deuterium uptake was analyzed for 68 STAT3 peptides representing 71% sequence coverage, and mapped onto the crystal structure of STAT3. This analysis precisely defined the binding epitope for BP-5-087 within the STAT3 SH2 domain. We next tested the effects of BP-5-087 in several myeloid malignancies using relevant disease models. (i) CML stem and progenitor cells from TKI-resistant patients without kinase domain mutations were treated with BP-5-087 ex vivo, using short-term liquid culture, clonogenic and LTC-IC assays. BP-5-087 treatment significantly reduced colony formation by CML stem and progenitor cells (p<0.01), with no effect on normal human CD34+ cord blood (CB) cells. (ii) Similarly, BP-5-087 also increased apoptosis and reduced viability (p<0.05) of primary AML blasts treated ex vivo with BP-5-087 for 72 hours in liquid culture. (iii) CD34+ cells from patients with myelofibrosis were also treated with BP-5-087 in clonogenic assays, and similar to CML, BP-5-087 reduced myeloid colony formation, although to a lesser extent. The in vivo activity of BP-5-087 was next evaluated in a murine model of JAK2 V617F-induced MPN. Briefly, Balb/c bone marrow was transduced with JAK2 V617F-GFP, followed by injection into lethally irradiated recipients. After disease induction, mice were treated with BP-5-087 (25 mg/kg) by once-daily oral gavage. No toxicities were observed after 40 days of treatment in BP-5-087-treated mice. While BP-5-087 did not significantly reduce the percentage of GFP+ cells, there was a 41% reduction of spleen weight in BP-5-087-treated mice compared to vehicle-treated controls (p<0.05). Post study analysis revealed BP-5-087 plasma concentrations <1 μM, suggesting that insufficient bioavailability contributed to the modest in vivo effects. To advance the lead optimization of our STAT3 inhibitor series, we instituted a comprehensive screening cascade. We first developed a computational model (quantitative structure-activity relationship, QSAR) to guide and prioritize selection of new inhibitor candidates for synthesis. Compounds are initially ranked using a methanethiosulfonate (MTS)-based cell viability assay in a TKI-resistant, STAT3-dependent CML cell line (AR230R). Inhibition of STAT3 is confirmed using a cell-based STAT3 reporter assay and an in vitro FP-based binding assay. Optimization of potency is balanced by the goals of reducing molecular weight (MW) and calculated LogP (cLogP) compared to BP-5-087 (MW: 694.8; cLogP: 7.3). Compounds with improvements in these categories are then subject to toxicity testing utilizing clonogenic assays with CD34+ CB cells. Non-toxic compounds are evaluated for their pharmacokinetic profile in Balb/c mice and tested for activity in primary samples from CML, AML and MPN patients. These activities have directed us to a lead compound, AM-1-124, which displays significant improvements in potency, MW, cLogP, and in vivo half-life compared to BP-5-087. AM-1-124 had minimal effects in the CB toxicity assay and induced apoptosis in primary AML patient samples at 2-fold lower concentrations than BP-5-087. With AM-1-124 as our current lead compound, we are continuing our iterative evaluation of novel STAT3 inhibitors utilizing our screening cascade. Design and testing of optimized, orally active inhibitors will enable further evaluation of STAT3 as a target in animal models of myeloid leukemia and will justify the clinical development of these compounds for patients in need of new targeted therapies. Disclosures Deininger: BMS, Novartis, Celgene, Genzyme, Gilead: Research Funding; BMA, ARIAD, Novartis, Incyte, Pfizer: Advisory Board, Advisory Board Other; BMS, ARIAD, Novartis, Incyte, Pfizer: Consultancy.

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Safo, Martin K., Piyusha P. Pagare, Mohini Ghatge, Carla Casu, Valentina Ghiaccio, Nancy Anabaraonye, Xiaomeng Xu et al. „PP-14, a Novel Structurally-Enhanced Antisickling Allosteric Hemoglobin Effector, Increases Oxygen Affinity and Disrupts Hemoglobin S Polymer Formation“. Blood 134, Supplement_1 (13.11.2019): 73. http://dx.doi.org/10.1182/blood-2019-128646.

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We have previously designed and investigated novel allosteric effectors of hemoglobin (AEHs), as potential targeted treatment of sickle cell disease (SCD). In general, AEHs transiently covalently bind to hemoglobin (Hb), increase its affinity for O2, increasing the fraction of oxygenated sickle Hb (HbS), thus reducing HbS polymerization and countering red blood cell (RBC) sickling. In the current study, we designed a novel class of AEH molecules, incorporating a secondary mechanism of action (MOA), which is independent of Hb O2-affinity by interacting with the F-helix of deoxygenated HbS to directly destabilize its polymerization. Here, we report current results from our in-vitro and in-vivo studies with a representative AEH compound (PP-14). First, we assessed the anti-sickling properties in-vitro by incubating 0.5, 1, and 2 mM of PP-14 with whole blood suspensions from a subject with homozygous SCD (SS, hematocrit: 20%) under hypoxic conditions, with subsequent RBC sickling assessment by microscopy. Next, we subjected the samples to anoxia (100% N2 gas) to demonstrate the O2-affinity-independent antisickling mechanism. Subsequently, we tested residual samples for the degree of Hb modification (i.e., HbS-AEH adduct formation) and O2-affinity (p50) shifts. In a second experiment to further assess the secondary MOA, we subjected SS blood samples treated with various concentrations of PP-14 to hypoxia in the Hemox analyzer, which permitted us to obtain aliquot samples at defined pO2 values to establish pO2-dependent sickling. Additionally, we conducted in silico and in-vitro ADME studies to evaluate possible metabolic inhibition of a panel of CYP enzymes. Finally, we conducted a preliminary in-vivo PK/PD study in wild-type mice administered single doses of PP-14 via the oral (P.O.: 100-200 mg/kg) and intraperitoneal (I.P.: 75 mg/kg) routes. Serial blood samples were collected for up to 52 h after P.O., and up to 30 h after I.P. administration, and samples were assayed to quantify PP-14 concentrations. Residual blood samples were assayed for in-vivo Hb-AEH adduct formation, and the corresponding change in O2-affinity (Δp50, %). Our in-vitro studies demonstrated concentration-dependent inhibition of cell sickling of 25.5±11%, 44.4±3.8% and 90.8±1%, at 0.5, 1 and 2 mM of PP-14, respectively. HbS was modified correspondingly (38.9±9%, 55.7±4.9 %, and 92.4±9.8%), and was correlated linearly with the left-shift in OEC (Δp50 values of 11.3±5.1%, 29.0±13.2%, and 67.5±8.2%). Importantly, the antisickling effect was sustained under anoxic conditions (100% N2), strongly supporting the notion of a secondary, O2-affinity-independent MOA. Furthermore, we observed a dose-dependent delay in sickling, with initiation of sickling recorded at a pO2 level of 40 mmHg in absence of PP-14; and at 30 and 20 mmHg at 0.5, and 1 mM PP-14 concentrations, respectively. Complete inhibition of sickling was observed at 2 mM PP-14 through the lowest recorded pO2 level of 1.5 mmHg, a unique, effect not previously observed in any analogous AEH. In-vitro partitioning studies demonstrated that >90% of PP-14 partitioned into the RBC compartment when whole blood was incubated with 100-300 µM concentrations. Metabolic studies using pooled human liver microsomes (HLM) and isozyme-specific probe substrates suggested that up to 100 µM PP-14 did not inhibit CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4 or CYP2B6. Wild-type mice after I.P. administration of PP-14 (75 mg/kg, n=5) showed peak concentrations in blood at 7 hrs (416.3±81.2 µM), with corresponding PD effects (Δp50 of 41.6±13.5%; modified Hb levels of 43.6±8.0%). Orally-treated mice had peak drug concentrations after 10-24 hrs, (~150 µM at 200 mg/kg, n= 2), with corresponding PD effects (Δp50 of 36.5±7.0%; modified Hb levels of 28.8±4.9%), which declined by 52 hrs. Overall, our data confirm that PP-14 is novel antisickling AEH with a secondary, O2-independent MOA in addition to the primary O2-dependent effect, as demonstrated by the inhibition of sickling under anoxic conditions. Additionally, PP-14 showed: excellent partitioning into the RBC compartment; acceptable in-silico ADME properties and in-vivo oral bioavailability; PD effects; and low liability for metabolic drug-drug interactions. Further studies to investigate formal detailed pharmacokinetic properties, and biological activity after single- or repeat-doses in a SCD mouse model are ongoing. Disclosures Safo: Sanofi: Consultancy, Research Funding; Virginia Commonwealth University: Patents & Royalties. Pagare:Virginia Commonwealth University: Patents & Royalties. Ghatge:Virginia Commonwealth University: Patents & Royalties. Rivella:Meira GTx, Ionis Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Disc medicine, Protagonist, LIPC, Meira GTx: Consultancy. Hines:Functional Fluidics: Equity Ownership. Liu:Functional Fluidics: Employment. Zhang:Virginia Commonwealth University: Patents & Royalties. Venitz:Virginia Commonwealth University: Patents & Royalties. Abdulmalik:The Children's Hospital of Philadelphia: Patents & Royalties: Provisional Patent.

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Zhang, Jie, und Zhenhao Zhou. „Preclinical Study of a Novel Tri-Specific Anti-CD3/CD19/CD20 T Cell-Engaging Antibody As a Potentially Better Treatment for NHL“. Blood 136, Supplement 1 (05.11.2020): 22. http://dx.doi.org/10.1182/blood-2020-140154.

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CD20 targeted therapy by means of anti-CD20 mAb is currently the most important regimen for treating B cells malignancies. However, 1-2% of B-cell lymphoma patients test negative for CD20. Besides, it has been reported in several studies that CD20 expression was down-regulated in over 20% of CD20-positive DLBCL patients that had relapsed/progressed after R-CHOP regimen. The limited prognosis for these patients poses a substantial unmet medical need. A new class of "1:2" format CD3 x CD20 bispecific antibodies emerged aiming for increased tumor antigen avidity and enhanced tumor cell killing, however, its advantages over conventional "1:1" format CD3 x CD20 antibodies have yet to be revealed in clinical trials. CMG1A46 is a 151 KD IgG-like "1:(1+1)" tri-specific antibody constructed on Chimagen's TRIAD platform. It simultaneously targets CD3 on T cell and two different biomarkers - CD20 and CD19 (abundancy of which proven to be intact post CD20-targeted treatment) - on tumor cells, recruiting T cells to kill tumor cells expressing CD19 and/or CD20. CMG1A46 is designed to target not only conventional CD19+CD20+ DLBCL, but also CD20-CD19+ DLBCL and DLBCL with trace to low expression of CD20 owing to its high avidity for tumor cells from 2 binders for CD19 and CD20 respectively. In vitro, CMG1A46 was shown to mediate tumor cell lysis by human PBMCs in a dose-dependent manner with EC50 around 0.3 pM. CMG1A46 was shown to have superior potency and safety (based on target-independent T cell activation) when compared to CD3 x CD20 bispecific antibodies with the conventional "1:1" IgG-based format. The antibody was able to induce potent tumor lysis in cells expressing both CD19 and CD20, and in cells expressing CD19 or CD20 alone. In vivo, 1A46 displayed potent tumor-suppressing activity in human PBMC-engrafted NOD mouse models and induced fast regression of large (CD19+CD20+) Jeko-1 lymphoma and (CD19+CD20-) A20-hCD19 tumors of ~100mm3. Remarkably, CMG1A46 can be administrated at the dosage 6 times as high as conventional CD3 x CD20 bispecific antibodies (3mg/kg for CMG1A46, 0.5mg/kg for conventional) and conferred even higher anti-tumor potency without any noticeable increase in toxicity (as evidenced by body weight of the animals and cytokine levels/T cell counts in serum post last administration). Pharmacokinetic studies in cyno monkeys show that when administrated at 1mpk CMG1A46 has a half-life that is over 70 hours in serum. After initial induction doses, weekly administration is able to maintain high circulating levels of the molecule. Dosages up to 10mpk do not lead to significant adverse effects. CMG1A46 treatment resulted in fast and complete elimination of B cells in peripheral blood within 24 hours after the first administration. Peripheral B cell elimination sustained for at least 28 days after last administration at 1mpk. B cell depletion was paralleled by transient decrease of T-cell counts in the peripheral blood and by the peak of cytokine release 4-8 hours after the first administration, followed by rapid recovery and return to baseline levels at 24 hours post treatment. Accordingly, CD3 receptor occupancy (RO) transiently increased during the induction phase and fell back to and sustained at a low level of around 20-30%. These studies show that CMG1A46 is a novel CD19/CD20-targeting T cell-engaging tri-specific antibody with very promising anti-tumor activity. In both in vitro and in vivo experiments, CMG1A46 demonstrated superior potency and safety compared to other CD3 x CD20 bispecific antibodies with the conventional "1:1" IgG format. Preliminary study in cyno monkeys suggested IgG-like half-life in serum and manageable toxicity. Taken together, the preclinical data strongly support for clinical testing of CMG1A46 in patients with CD20+ cancers. Phase 1 trial of the molecule is scheduled to start by April 2021. Disclosures No relevant conflicts of interest to declare.

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Morelli, Eugenio, Lavinia Biamonte, Cinzia Federico, Nicola Amodio, Maria Teresa Di Martino, Maria Eugenia Gallo Cantafio, Martina Manzoni et al. „Therapeutic vulnerability of multiple myeloma to MIR17PTi, a first-in-class inhibitor of pri-miR-17-92“. Blood 132, Nr. 10 (06.09.2018): 1050–63. http://dx.doi.org/10.1182/blood-2018-03-836601.

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Key Points First-in-class MIR17PTi enables 1-shot downregulation of miR-17-92 in vitro and in vivo, with favorable pharmacokinetic profile. MIR17PTi affects homeostatic MYC/miR-17-92 FFLs in MM cells, resulting in strong anti-MM activity.

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Abuhelwa, Ahmad Y., Stuart Mudge, Richard N. Upton und David J. R. Foster. „Population in vitro–in vivo pharmacokinetic model of first-pass metabolism: itraconazole and hydroxy-itraconazole“. Journal of Pharmacokinetics and Pharmacodynamics 45, Nr. 2 (17.11.2017): 181–97. http://dx.doi.org/10.1007/s10928-017-9555-8.

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Sysuev, Boris B., und Damir K. Salakhetdinov. „In vivo study of pharmacokinetic parameters of a new combination drug based on citicoline and memantine“. Research Results in Pharmacology 7, Nr. 2 (15.06.2021): 23–30. http://dx.doi.org/10.3897/rrpharmacology.7.60380.

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Introduction: Cognitive impairment (dementia) is one of the most common pathologies with increasing numbers of patients. Most often they are the symptoms of Alzheimer’s disease and vascular brain diseases, for which such drugs as memantine and citicoline are used. The development of a combination drug with these active pharmaceutical ingredients can significantly increase the effectiveness of therapy. Materials and methods: The pharmacokinetics of memantine and citicoline combination drug was evaluated in comparison with the marketed drugs (reference drugs) of these pharmaceutical substances approved for medical use by determining their content in blood plasma of experimental animals after a single oral administration. Results: Seventy-two hours after the administration of memantine drug, about 5% and 17% of the maximum concentration of memantine released from Akatinol Memantine and the developed combination drug were found in blood plasma, respectively. By the 120th hour after the beginning of the experiment, no memantine was detected in blood plasma of any animal. By the 24th hour after the beginning of the experiment, about 46% and 50% of the maximum concentration of citicoline released from the developed combination drug and the Ceraxon drug were found in blood plasma of the rabbits, respectively. Discussion: It was detected that the amounts of released memantine and citicoline from the developed combination drug exceeded the amounts of the appropriate pharmaceutical substances released from the reference drugs. The bioavailability of these substances from the developed combination drug was higher than from the marketed mono formulations used as reference drugs. Conclusion: Based on the obtained results of memantine and citicoline concentrations in bioassays, the main pharmacokinetic parameters of the studied preparations were calculated, the results of which showed the superiority of the developed combination drug over the reference drugs.

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Chernykh, I. V., A. V. Shchulkin, E. N. Yakusheva, M. V. Gatsanoga und N. M. Popova. „ANALYSIS OF ATTRIBUTION OF NOOPEPT TO SUBSTRATES AND MODULATORS OF FUNCTIONAL ACTIVITY OF ABCB1-PROTEIN IN IN VIVO EXPERIMENT“. I.P.Pavlov Russian Medical Biological Herald 25, Nr. 1 (31.03.2017): 30–41. http://dx.doi.org/10.23888/pavlovj2017130-41.

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In the article the influence of nootropic drug Noopept (N-phenyl-acetyl-L-prolylglycine ethyl ester) on the functional activity of ABCB1-protein is analyzed and attribution of this drug to the transport protein substrates is studied on male Chinchilla rabbits. Functioning of the transport protein was estimated by the pharmacokinetics of its marker substrate - fexofenadine. Fexofenadine was introduced intragastrically one time in the dose 67,5 mg/kg b.w. before and after 14-day introduction of Noopept in the dose 10 mg/kg b.w. 3 times a day. The quantity of the substance was determined by HPLC method according to the previously developed procedure.Belonging of Noopept to ABCB1-protein substrates was estimated by comparison of its pharmacokinetic parameters before and after a course of introduction of verapamil (the known inhibitor of the ABCB1-protein) into male rabbits in the dose 20 mg/kg b.w. 3 times a day. The pharmacokinetics of Noopept was studied by the original HPLC method.It was found that the course of Noopept introduction did not lead to any reliable changes in the pharmacokinetic parameters of the ABCB1-protein marker substrate - fexofenadine, which may evidence preservation of the functional activity of the given transport protein at the initial level. It was also found that the pharmacokinetics of Noopept remained unchanged after a course of introduction of ABCB1-protein inhibitor - verapamil - in to the male rabbits, that is, Noopept is not a substrate of the given transport protein.

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Cheng, Lijun, und Yang Deng. „Characterization by HPLC of p-Hydroxybenzyl Alcohol Biotransformation to Gastrodin In Vivo“. Natural Product Communications 16, Nr. 9 (September 2021): 1934578X2110350. http://dx.doi.org/10.1177/1934578x211035069.

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Gastrodin (GAS) and its aglycone, p-hydroxybenzyl alcohol (HBA), are both bioactive compounds extracted from Gastrodia elata Blume (GEB). In the current Chinese pharmacopoeia, they are regarded as quality control markers for GEB. In this study, we developed a high-performance liquid chromatography method coupled with a diode array detector to quantify GAS and HBA concentrations in plasma following oral ingestion by rats. For the first time, GAS was detected in vivo after HBA administration. GAS and HBA both had similar pharmacological effects, but the influence of the glucose moiety resulted in different pharmacokinetic characteristics. In this study, the effects of GAS and HBA at different administration durations were investigated in zebrafish larvae. These compounds were found to induce a sedative effect but had different onset times. In conclusion, a biotransformation of HBA to GAS could be observed in the rats. This may be a new insight into the pharmacokinetic characteristics of these bioactive compounds and also relates to the different ways in which they take effect.

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Ahn, Sung-Hoon, Tae-Hwe Heo, Hyun-Sik Jun und Yongseok Choi. „In vitro and in vivo pharmacokinetic characterization of LMT-28 as a novel small molecular interleukin-6 inhibitor“. Asian-Australasian Journal of Animal Sciences 33, Nr. 4 (01.04.2020): 670–77. http://dx.doi.org/10.5713/ajas.19.0463.

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Objective: Interleukin-6 (IL-6) is a T cell-derived B cell stimulating factor which plays an important role in inflammatory diseases. In this study, the pharmacokinetic properties of LMT-28 including physicochemical property, in vitro liver microsomal stability and an in vivo pharmacokinetic study using BALB/c mice were characterized.Methods: LMT-28 has been synthesized and is being developed as a novel therapeutic IL-6 inhibitor. The physicochemical properties and in vitro pharmacokinetic profiles such as liver microsomal stability and Madin-Darby canine kidney (MDCK) cell permeability assay were examined. For in vivo pharmacokinetic studies, pharmacokinetic parameters using BALB/c mice were calculated.Results: The logarithm of the partition coefficient value (LogP; 3.65) and the apparent permeability coefficient values (Papp; 9.7×10–6 cm/s) showed that LMT-28 possesses a moderate-high cell permeability property across MDCK cell monolayers. The plasma protein binding rate of LMT-28 was 92.4% and mostly bound to serum albumin. The metabolic half-life (t1/2) values of LMT-28 were 15.3 min for rat and 21.9 min for human at the concentration 1 μM. The area under the plasma drug concentration-time curve and Cmax after oral administration (5 mg/kg) of LMT-28 were 302±209 h∙ng/mL and 137±100 ng/mL, respectively.Conclusion: These data suggest that LMT-28 may have good physicochemical and pharmacokinetic properties and may be a novel oral drug candidate as the first synthetic IL-6 inhibitor to ameliorate mammalian inflammation.

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Shearstone, Jeffrey R., Apurva Chonkar, Kailash Bhol, Simon S. Jones und Matt Jarpe. „The Histone Deacetylase 1 and 2 (HDAC1/2) Inhibitor ACY-957 Increases Epsilon (HbE) and Gamma (HbG) Globin mRNA in the Peripheral Blood of Non-Anemic Rats and Monkeys“. Blood 126, Nr. 23 (03.12.2015): 3378. http://dx.doi.org/10.1182/blood.v126.23.3378.3378.

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Abstract Elevated levels of HbG mRNA, leading to the formation of fetal hemoglobin, is known to ameliorate disease severity in sickle cell and β-thalassemia patients. We have previously shown that the small molecule ACY-957 is a selective inhibitor of HDAC1/2 which induces HbE and HbG in cultured human primary CD34+ cells (Shearstone et al, ASH Annual Meetings 2012-14). In this work, we describe the pharmacokinetics and HbE/HbG induction following once daily oral dosing of ACY-957 in rat and monkey. To determine the duration of ACY-957 exposure required to induce HbE and HbG in vivo, we first tested ACY-957 in drug washout experiments performed in cultured primary erythroid progenitors. The aminobenzamide class of HDAC inhibitors, such as ACY-957, are known to have slow on rates for HDAC1/2 (Kral et al, Biochemistry 2014; Lauffer et al, J Biol Chem 2013). We found that a 6 h pulse of ACY-957 (1 μM) resulted in undetectable increases in histone H3 lysine 9 acetylation (H3K9ac) and that 4 or 8 h pulses of ACY-957 (1 μM) resulted in undetectable HbE and HbG induction. However, continued exposure resulted in a 2.5-fold and 7-fold increase in H3K9ac after 24 and 48 h of incubation, respectively, leading to a time-dependent increase in HbE and HbG. Based on this data, we hypothesized that in vivo studies would require ACY-957 levels of 1 μM for 24 h in order to observe elevated HbE and HbG. Non-fasted Sprague Dawley rats or cynomolgus monkeys received a single oral dose of 20 mg/kg or 12.5 mg/kg ACY-957, respectively, and pharmacokinetic analysis yielded comparable results with T1/2 = 11.8 and 10.9 h, Cmax = 7.8 and 2.4 μM, and Tmax = 5.3 and 4.0 h, in rat and monkey, respectively. At 24 h post dose, ACY-957 plasma levels in rat and monkey were 1.6 and 0.6 μM, respectively. These findings suggested that the targeted drug exposure could be met with a single daily oral dose of ACY-957. Since ACY-957 induced HbE in cultured human primary erythroid progenitors, we attempted to measure HbE induction in rat as a surrogate marker for HbG in primate. Rats were dosed with 0, 10 or 30 mg/kg (n=4 per group) by oral gavage, once daily for 6 days, followed by a 13 day washout period. Peripheral blood was sampled every 3 days for isolation of total RNA. Complete blood counts were performed on day 0, 6 and 18. The low and high dose groups showed ACY-957 plasma levels of 1.3 or 5.2 μM, respectively, at 24 h post final dose. No abnormal clinical signs were found during the in-life phase, although a minor, reversible delay in rat weight gain was observed in the high dose group. White blood cells were suppressed by 33% and 68% at day 6 in low and high dose groups, respectively, but recovered to baseline levels by day 18. ACY-957 administration led to a dose-dependent increase in HbE relative to HbB that was detectable at day 3, peaked at day 6, and returned to baseline levels by day 9. Maximum induction of HbE was 2-fold and 5.6-fold for the low and high dosing groups, respectively, relative to animals receiving vehicle only. Next, monkeys were dosed at 0, 25 or 75 mg/kg (n=3 per group) by oral gavage, once daily for 5 days, followed by a 14 day washout period. Peripheral blood was sampled every 2 to 3 days for isolation of total RNA and analysis of complete blood counts. The low and high dose groups showed ACY-957 plasma levels of 1.9 or 8.0 μM, respectively, at 24 h post final dose. No abnormal clinical signs were found during the in-life phase. White blood cells were suppressed by 25% and 61% at day 5, but recovered to baseline levels by day 9. ACY-957 administration led to a dose-dependent increase in HbE and HbG relative to HbB that was detectable at day 5, peaked at day 7, and returned to baseline levels by day 12. Maximum induction of HbG was 2.2-fold and 7.2-fold for the low and high dosing groups, respectively, relative to animals receiving vehicle only. These results demonstrate that ACY-957 induces HbE in rat and HbG in monkey to a similar extent. ACY-957 appeared well tolerated in both animals, although a reversible suppression of white blood cells was observed. Together, these findings suggest that optimization of dose and schedule could be performed in rats by monitoring HbE as a surrogate for HbG in primates. The optimized regime could then be validated in cynomolgus monkey. Accordingly, we have initiated experiments that explore the effects of several different ACY-957 dose schedules on HbE induction and white blood cell suppression in rats during a 4 week dosing and 2 week recovery period, which will also be presented. Disclosures Shearstone: Acetylon Pharmaceuticals, Inc.: Employment, Equity Ownership. Chonkar:Acetylon Pharmaceuticals, Inc.: Employment, Equity Ownership. Bhol:Acetylon Pharmaceuticals, Inc.: Employment, Equity Ownership. Jones:Acetylon Pharmaceuticals, Inc.: Employment, Equity Ownership. Jarpe:Acetylon Pharmaceuticals, Inc.: Employment, Equity Ownership.

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Širmenis, Raimondas, Antanas Kraniauskas, Rasa Jarašienė, Daiva Baltriukienė, Audronė Kalvelytė und Virginija Bukelskienė. „Recovery of Infarcted Myocardium in an In Vivo Experiment“. Medicina 47, Nr. 11 (04.12.2011): 88. http://dx.doi.org/10.3390/medicina47110088.

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Acute myocardial infarction leads to the loss of functional cardiomyocytes and structural integrity. The adult heart cannot repair the damaged tissue due to inability of mature cardiomyocytes to divide and lack of stem cells. The aim of this study was to evaluate the efficiency of introduced autologous skeletal musclederived stem cells to recover the function of acutely infarcted rabbit heart in the early postoperative period. Material and Methods. As a model for myocardium restoration in vivo, experimental rabbit heart infarct was used. Autologic adult myogenic stem cells were isolated from skeletal muscle and propagated in culture. Before transplantation, the cells were labeled with 4´,6-diamidino-2-phenylindole and then, during heart surgery, introduced into the rabbit acutely infarcted myocardium. Postoperative cardiac function was monitored by recording electrocardiograms and echocardiograms. At the end of the experiment, the efficiency of cell integration was evaluated histologically. Results. Rabbit cardiac function recovered after 1 month after the induction of experimental infarction both in the control and experimental groups. Therefore, the first month after the infarction was the most significant for the assessment of cell transplantation efficacy. Transplanted cell integration into infarcted myocardium was time- and individual-dependent. Evaluation of changes in left ventricular ejection fraction after the induction of myocardial infarction revealed better recovery in the experimental group; however, the difference among animals in the experimental and control groups varied and was not significant. Conclusions. Autologous myogenic stem cells repopulated infarcted myocardium with different efficiency in each individual. This variability may account for the observed difference in postoperative cardiac recovery in a rabbit model.

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Váradi, Hermenean, Gesztelyi, Jeney, Balogh, Majoros, Malanga et al. „Pharmacokinetic Properties of Fluorescently Labelled Hydroxypropyl-Beta-Cyclodextrin“. Biomolecules 9, Nr. 10 (20.09.2019): 509. http://dx.doi.org/10.3390/biom9100509.

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2-Hydroxypropyl-beta-cyclodextrin (HPBCD) is utilized in the formulation of pharmaceutical products and recently orphan designation was granted for the treatment of Niemann–Pick disease, type C. The exact mechanism of HPBCD action and side effects are not completely explained. We used fluorescently labelled hydroxypropyl-beta-cyclodextrin (FITC-HPBCD) to study its pharmacokinetic parameters in mice and compare with native HPBCD data. We found that FITC-HPBCD has fast distribution and elimination, similar to HPBCD. Interestingly animals could be divided into two groups, where the pharmacokinetic parameters followed or did not follow the two-compartment, first-order kinetic model. Tissue distribution studies revealed, that a significant amount of FITC-HPBCD could be detected in kidneys after 60 min treatment, due to its renal excretion. Ex vivo fluorescent imaging showed that fluorescence could be measured in lung, liver, brain and spleen after 30 min of treatment. To model the interaction and cellular distribution of FITC-HPBCD in the wall of blood vessels, we treated human umbilical vein endothelial cells (HUVECs) with FITC-HPBCD and demonstrated for the first time that this compound could be detected in the cytoplasm in small vesicles after 30 min of treatment. FITC-HPBCD has similar pharmacokinetic to HPBCD and can provide new information to the detailed mechanism of action of HPBCD.

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Liu, Kena, Pingjiang Ge, Xiaoli Sheng, Jie Jiang und Huabiao Qin. „Survival in Vivo Canine Phonation Model Without Stimulation“. Annals of Otology, Rhinology & Laryngology 127, Nr. 3 (03.01.2018): 178–84. http://dx.doi.org/10.1177/0003489417751473.

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Objectives: We describe a survival nonstimulated in vivo canine phonation model using distending laryngoscope, cramp frame, and constant humidified glottal airflow to elicit phonation. Methods: Five beagle dogs were involved in this study. One cuffed endotracheal tube was placed below the glottis through the tracheotomy and delivered humidified airflow to the glottis. Arytenoids approximation was maintained using a clamp under the distending laryngoscope. Acoustic and aerodynamic parameters were measured using synchronous signal collection system and analysis software. Vocal oscillation also was examined using stroboscope laryngeal imaging. Results: For the nonstimulated in vivo phonation animal, the sound intensity and fundamental frequency were 78.3 ± 6.8 dB and 127.6 ± 29.2 Hz in the first experiment and 82.9 ± 6.6 dB and 175.2 ± 4.4 Hz 4 weeks later. The aerodynamic analysis revealed the mean subglottal phonation threshold pressure (PTP) and phonation threshold flow (PTF) were 8.5 ± 4.0 cmH20 and 683.0 ± 356.4 mL/s in the first experiment and 16.1 ± 8.6 cmH20 and 384.8.0 ± 230.6 mL/s in the second experiment 4 weeks later. Stroboscope image revealed sustained vocal vibration during great airflow delivery to glottis in the phonation animal model. Conclusions: We developed a survival nonstimulated in vivo phonation canine model that allows the study of long-term animal phonation study as its own control.

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Belhadj-Tahar, Hafid, Rachid Boumahdi und Marie-hélène Darbieu. „Conceptualisation of Diagnostic Agents: From Empirical In Vivo Screening to Rational In Vitro Predictive Parameters“. Alternatives to Laboratory Animals 28, Nr. 2 (März 2000): 303–14. http://dx.doi.org/10.1177/026119290002800201.

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A new rational conceptualisation protocol in new isotopic diagnostic agents has been designed to avoid systematic empirical in vivo screening. This protocol is based on multiple regression analysis, in order to determine the pharmacokinetic model capable of explaining in the best possible way the in vivo behaviour of molecules injected into an organism. Nine technetium complexes (99mTc-L) were synthesised from aminothiol ligand vectors. These complexes were characterised in terms of their physical, chemical and biological in vitro properties, i.e. lipophilicity (P), free fraction unbound to plasmatic proteins (Fup), the fraction unbound to blood cells (FuCb), and membrane adsorption fraction (Fad), an original factor assessed in vitro. Thus, two pharmacokinetic models were tested. The first takes into account the parameters classically used in pharmacokinetics (P, Fup, FuCb), and the second, in parallel with the first, includes the membrane adsorption rate (polar/apolar/polar membrane model). According to the phenomenon of tissular distribution, the explanatory power of the second model, including the Fad, is radically greater than that of the classical model. The comparative adjusted coefficient of determination ([Formula: see text]2) of the model, including the Fad versus [Formula: see text]2 of the first model, are heart (91%/6%), liver (89%/47%), spleen (64%/44%), lung (78%/26%), kidney (70%/33%) and brain (73%/8%), respectively. In addition, as for the myocardium, the membrane adsorption factor seems to be the only predictive factor of the affinity between the myocardium and neutral or cationic molecules. This refutes the generally held view that only cationic molecules could have an affinity with the heart.

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Thaper, Daksh L., Ravi Munuganti, Shaghayegh Nouruzi, Sahil Kumar, Soojin Kim, Sepideh Vahid, Olena Sivak et al. „First-in-field small molecule inhibitors targeting BRN2 as a therapeutic strategy for small cell prostate cancer.“ Journal of Clinical Oncology 37, Nr. 7_suppl (01.03.2019): 260. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.260.

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260 Background: Resistance to newly developed androgen receptor pathway inhibitors (ARPIs), such as Enzalutamide (ENZ), rapidly emerges and patients generally die within two years. In particular, a subset of patients who relapse following ARPI therapy exhibit lineage switching whereby tumours shed their dependence on AR signaling and emerge with neuroendocrine features. These tumours, termed treatment induced neuroendocrine prostate cancer (t-NEPC), carry an extremely poor prognosis and, to date, treatment remains decades old cytotoxic chemotherapies; therefore, targeted therapies are desperately needed. Recently our group identified the neural transcription factor BRN2 as a major clinically relevant driver of NEPC and aggressive tumor growth, both in vitro and in vivo, suggesting targeting BRN2 is a promising strategy to prevent neuroendocrine differentiation or treat NEPC. Methods: Study the effects of BRN2 inhibition using siRNA, small molecule inhibitors (BRN2i) and CRISPR K/O models. The efficacy of the small molecules was examined using reporter assays, florescence polarization assays, Biolayer Interferometry, DARTS, chromatin fractionation, RNA-seq and ChIP-seq. Pharmacokinetic studies measured stability and bioavailability of the molecules and in-vivo efficacy is to be measured in NCI-H660 xenograft model. Results: Inhibition of BRN2 drastically reduced cell proliferation in NEPC cell lines 42DENZR and NCI-H660 cell lines. Targeting BRN2 with our first-in-field small molecule inhibitors lead to downregulation several known targets in NEPC like EZH2, ASCL1, SOX2 and PEG10. Treatment with BRN2i reduced recruitment of BRN2 to the chromatin by approximately 93% within 16 hours. Moreover, these BRN2 inhibitors displayed adequate pharmacokinetic properties and reduced NEPC proliferation in vivo. Conclusions: No therapies exist for highly lethal NEPC. Hence, the described work aims to lay the pre-clinical foundation for the integration of BRN2 targeted therapies into the treatment landscape to improve survival for patients suffering from small cell prostate cancer.

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Chen, Duofang, Jimin Liang und Kui Guo. „Temporal Unmixing of Dynamic Fluorescent Images by Blind Source Separation Method with a Convex Framework“. Computational and Mathematical Methods in Medicine 2015 (2015): 1–12. http://dx.doi.org/10.1155/2015/713424.

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By recording a time series of tomographic images, dynamic fluorescence molecular tomography (FMT) allows exploring perfusion, biodistribution, and pharmacokinetics of labeled substances in vivo. Usually, dynamic tomographic images are first reconstructed frame by frame, and then unmixing based on principle component analysis (PCA) or independent component analysis (ICA) is performed to detect and visualize functional structures with different kinetic patterns. PCA and ICA assume sources are statistically uncorrelated or independent and don’t perform well when correlated sources are present. In this paper, we deduce the relationship between the measured imaging data and the kinetic patterns and present a temporal unmixing approach, which is based on nonnegative blind source separation (BSS) method with a convex analysis framework to separate the measured data. The presented method requires no assumption on source independence or zero correlations. Several numerical simulations and phantom experiments are conducted to investigate the performance of the proposed temporal unmixing method. The results indicate that it is feasible to unmix the measured data before the tomographic reconstruction and the BSS based method provides better unmixing quality compared with PCA and ICA.

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Heinz, Stefan, Jörg Schüttrumpf, Jeremy Simpson, Rainer Pepperkok, Gerry Nicolaes, Daniela Abriss, Peter Milanov, Stefanie Roth, Erhard Seifried und Torsten Tonn. „Factor VIII-eGFP fusion proteins with preserved functional activity for the analysis of the early secretory pathway of factor VIII“. Thrombosis and Haemostasis 102, Nr. 11 (2009): 925–35. http://dx.doi.org/10.1160/th08-12-0807.

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SummaryConsidering the difficulty in detecting factor (F)VIII in vivo, fluorescently labelled FVIII protein provides a tool to analyse the intracellular localisation, bio distribution, and pharmacokinetics of the protein in living organisms. Here, we report the use of FVIII full length and B-domain deleted proteins, fused to enhanced green fluorescent protein (eGFP) at the C-terminus of the coagulation protein via a nine amino acid spanning linker. Comparison of the FVIII-eGFP fusion proteins to their unlabelled counterparts showed no impairment with respect to recombinant expression levels, intracellular processing, specific coagulant activity and decay at physiological temperature. Confocal live cell imaging demonstrated ER-Golgi-transport of B-domain deleted FVIII-eGFP in vesicular tubular carriers. Using temperature blocks and release experiments, imaging of FVIII-eGFP fusion proteins enabled for the first time the visualisation of the early secretory pathway of B-domain deleted FVIII in living cells and in particular highlighted the apparent deficit of active transport carriers, an observation consistent with the low rates of FVIII secretion seen in recombinant expression systems.

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