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Model-Informed Drug Development
Published in Wei Zhang, Fangrong Yan, Feng Chen, Shein-Chung Chow, Advanced Statistics in Regulatory Critical Clinical Initiatives, 2022
This block is oral dosage forms specific. This block describe the dissolution of oral dosage forms. There are three common dissolution models for modeling the dissolution of oral dosage forms: the Weibull model, Johnson model and z-factor model [39–41]:
Novel antiviral drug discovery strategies to tackle drug-resistant mutants of influenza virus strains
Published in Expert Opinion on Drug Discovery, 2019
Although no influenza drug identified through high throughput screening (HTS) has been FDA approved, the intrinsic value of HTS should not be underestimated. In drug discovery against influenza virus, HTS can be performed with two approaches: i) biochemical assays on purified viral targets, and ii) cell-based assays. The first approach can be used when target-based drug discovery is preferred by the investigators. The main advantage of this approach is an easy adaptation into HTS format as exemplified in NA inhibition [23], PB2 cap-binding inhibition [33] or PA endonuclease inhibition assay [34]. The second approach has been used to evaluate both the compound mediated CPE inhibition and the cytotoxicity of the compound, usually in 384 well multiplate format [35]. This approach has been well optimized in several institutes, and the reagents for determining the endpoint cell viability, such as luciferase-based reagent kits, neutral red solutions, or MTT, are readily available from commercial sources [35–37]. It is worth noting that in both the assays, it is important to optimize the assay conditions to achieve a Z-factor (a screening window coefficient) value above 0.5, S/N (signal-to-noise ratio) value above 10 and S/B (signal to background) value over 5 [38] (formula for calculating Z-factor and S/N value is shown in Figure 4) to ensure the high quality of assay results.
Adaptation of a microbead assay for the easy evaluation of traditional anti-sickling medicines: application to DREPANOSTAT and FACA
Published in Pharmaceutical Biology, 2018
Joran Villaret, Guillaume Marti, Frédérique Dubois, Karine Reybier, Noémie Gaudre, Mohamed Haddad, Alexis Valentin
The reproducibility of the assay at 30% hematocrit was verified by repeating the experiment for each column of the 96-well plate. Our results showed that the columns 1, 2, 3, 10, 11 and 12 present different values due to a centrifugal effect depending on the position of the well on the 96-well plate. For this reason, these columns were deleted from the working area. An analysis of variance (ANOVA) was performed on columns 4, 5, 6, 7, 8 and 9 (p value = 0.42) and demonstrated that the values obtained could not be considered as significantly different. Row A and H were also deleted from the working area to focus experiments in the middle of the plate, so to limit vertical centrifugal effects. On this working area, the calculated Z’ Factor was 0.92, indicating that the assay is fit for purpose.
A study of inhibitors of d -glycero-β-d -manno-heptose-1-phosphate adenylyltransferase from Burkholderia pseudomallei as a potential antibiotic target
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Suwon Kim, Seri Jo, Mi-Sun Kim, Dong Hae Shin
The screening of about 150 chemical compounds (Table S1) was performed with a malachite green assay method18. The principle of this method is: when SNTs transfer the AMP moiety from ATP to the heptose, ADP-d-glycero-β-d-manno-heptose and pyrophosphate (PPi) are produced. PPi was decayed into two phosphates by inorganic pyrophosphatase (IPP) and phosphates were measured by the malachite green method. β-d-Glucose-1-phosphate (βG1P) was purchased from Tokyo Chemical Industry Co. (Tokyo, Japan); TCI was used as a substrate because it is difficult to obtain the actual substrate, d-glycero-β-d-manno-heptose-1-phosphate (βH1P). The content of the α-form of this product was less than 0.1% in the current lot. A colour reagent of the malachite green method for phosphate detection was a mixture of ammonium molybdate ((NH4)6Mo7O24), malachite green solution and Tween 20 in the ratio 1:3:0.1. The mixture was filtered with a PVDF syringe filter and stood at room temperature (RT) for 1 h before use. All chemicals (25 μM) were tested for their inhibitory potential through a comparison of actual absorbances with control at 620 nm. The actual absorbance was obtained from the difference in absorbance between the reaction mixtures with and without BpHldC. The reaction mixture included 10 mM Tris–HCl (pH 7.5), 10 mM MgCl2, 0.04 unit IPP, and 0.025 mg ml−1BpHldC (1.3 µM). To evaluate the accuracy of the inhibitor screening, Z′ factor was determined to be 0.9 (n = 15). The results indicate that the accuracy of the enzyme inhibitor test using this method is excellent19.