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Synthesis, Enzyme Localization, and Regulation of Neurosteroids
Published in Sheryl S. Smith, Neurosteroid Effects in the Central Nervous System, 2003
Note: The human GABAR subunit combinations were recombinantly expressed in Xenopus oocytes and measured by two-electrode voltage clamp recordings. GABA was bath applied at an EC10 concentration, and EC50 is the concentration of the steroid required for 50% of the maximum enhancement observed for that receptor. Imax is the maximum potentiation of GABA by the steroid relative to the maximum of GABA alone. ND = not determined.
Voriconazole
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Michael Neely, Dionysios Neofytos
In a well-established murine model of disseminated candidiasis with C. albicans, the ratio of the 24-hour area under the free drug concentration-time curve to the minimum inhibitory concentration (AUC:MIC) was the parameter most linked to organism kill, with a mean target ratio of 24 (Andes et al., 2003). This is virtually identical to a proposed target ratio for A. fumigatus of 25, derived from a combination of in vitro, in vivo, and clinical data. (Siopi et al., 2014) The authors proposed a second, surrogate target that could be easier in practice to measure, which is a trough/MIC concentration ratio of 2. An earlier in vitro study found a target AUC:MIC of 38 for A. fumigatus, but higher target ratios of 53 and 72 were needed for A. flavus and A. terreus, respectively, emphasizing that targets may not be not uniform across species. (Al-Saigh et al., 2012) Recently, a novel pharmacokinetic-pharmacodynamic (PK-PD) target has been proposed using serum galactomannan as a surrogate for Aspergillus infection (Huurneman et al., 2016). Using 261 voriconazole and 33 galactomannan measurements from 12 children, the authors determined in a retrospective analysis that a 24-hour voriconazole steady-state AUC:EC50 ratio was significantly associated (P = 0.003) with the terminal galactomannan, where EC50 is the concentration of voriconazole required in an individual patient to obtain half-maximal decline in galactomannan (Huurneman et al., 2016). They chose EC50 because it is an in vivo measure of drug potency, which takes into account patient factors (e.g. immune function) and pathogen factors (e.g. MIC). Both AUC and EC50 can be estimated from measured plasma voriconazole and serum galactomannan.
Non-human primates in the PKPD evaluation of biologics: Needs and options to reduce, refine, and replace. A BioSafe White Paper
Published in mAbs, 2022
Karelle Ménochet, Hongbin Yu, Bonnie Wang, Jay Tibbitts, Cheng-Pang Hsu, Amrita V. Kamath, Wolfgang F. Richter, Andreas Baumann
Moreover, using an integrated PKPD modeling approach with the data from a PKPD study conducted in monkeys, Yang et al. demonstrated: 1) a strong correlation between in vivo RO EC50 and immunosuppressive activities assessed through the T cell-dependent antibody response (TDAR) to keyhole limpet hemocyanin (KLH) in monkeys, and 2) the relevance (comparable values) between in vivo RO EC50 and in vitro MLR EC50. This PKPD relationship established in NHPs laid the groundwork in defining MABEL and selecting a subsequent FIH dose. Since no significant immunosuppression was observed in monkeys at an average in vivo RO of ≤30% over approximately 28 days, the MABEL was defined as a target in vivo RO <10% at predicted maximum concentration (Cmax) in humans. In vivo RO EC10 is not yet available until clinical trials are conducted. Therefore, based on the established relevance between in vivo RO and in vitro MLR EC50, the latter at 10% (MLR EC10) was used to calculate a MABEL dose of 0.01 mg.43
Optimization of hydroxychloroquine dosing scheme based on COVID-19 patients’ characteristics: a review of the literature and simulations
Published in Xenobiotica, 2021
Eleni Karatza, George Ismailos, Markos Marangos, Vangelis Karalis
HCQ concentrations in the lungs have been reported to be significantly higher than the corresponding ones in plasma (Yao et al., 2020). Therefore, reaching HCQ blood concentrations of 1500 ng/ml assures that the EC50 concentrations are achieved within the main organ affected by the disease (Harapan et al., 2020). In addition, there is some evidence that the virus attacks red blood cells, rendering them incapable of transporting oxygen (Liu & Li, 2020) and T cells, decreasing their number significantly (Qin et al., 2020). Thus, a high loading dose providing an initial phase of high blood levels, followed by sparse small doses is anticipated to be both more efficacious and safer in comparison to a frequent low dose scheme. This can also be supported by both the pharmacokinetics of HCQ and by its time-dependent EC50, which resulted in 9-fold lower values after an incubation of 48 h, as compared to an incubation period of 24 h (Yao et al., 2020). Consequently, in a dosage regimen with a high initial dose followed by small maintenance doses, the viral load is expected to decrease during the initial phase, while the virus becomes more susceptible to the drug’s concentration, allowing, therefore, for a gradual decrease of the dose to be administered.
Influence of spray drying on bioactive compounds of blackberry pulp microencapsulated with arrowroot starch and gum arabic mixture
Published in Journal of Microencapsulation, 2020
Gislaine Ferreira Nogueira, Cyntia Trevisan Soares, Luiz Gabriel Pereira Martin, Farayde Matta Fakhouri, Rafael Augustus de Oliveira
The median effective concentration (EC50) is a widely-used parameter to estimate the antioxidant capacity. EC50 is the concentration that inhibits 50% of the DPPH* radicals in solution. The lower the EC50, the higher are the antioxidant activities found (Medina-Torres et al. 2016). As can be seen in Table 1, all samples were able to trap free radicals. Antioxidant activity in powders was significantly (p < .05) influenced by inlet air temperature, which presented negative linear effect and by encapsulating agent concentration, which presented negative linear and quadratic effect on high antioxidant activity determined by the DPPH assay (Table 2). Therefore, blackberry powders with high antioxidant capacity were produced with inlet air temperatures values and encapsulating agent concentration minimum and maximum tested (Figure 4(D)), following the same behaviour as the FRAP assays.