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Alternative Methods for Assessing the Effects of Chemicals in the Eye
Published in David W. Hobson, Dermal and Ocular Toxicology, 2020
Leon H. Bruner, John Shadduck, Diane Essex-Sorlie
When estimating an endpoint obtained from an in vitro test, it is important to generate and use all of the data available. For example, it is possible to generate an assay endpoint (usually an estimated ED50 value) based on a very limited number of test material concentrations.21 This type of evaluation has limits because it only provides a small part of all the information available from a full dose-response curve. If a well-defined dose-response curve is generated during the assay procedure, the ED50 concentration can be determined with precision, and other useful data such as the shape and slope of the dose-response curve can be obtained. These data, although not widely used by developers of in vitro alternatives, may provide a wealth of additional information on test substance characteristics that may be useful for making a safety assessment with the in vitro test. For example, dose-response curve slope data may be useful in grouping materials according to common modes of action for further evaluation. Also, the additional data may be useful for pointing the way to further experiments that will help elucidate the mechanism(s) by which the test materials irritate and injure target tissues.
Planning a Model-Based Bayesian Dose Response Study
Published in Mani Lakshminarayanan, Fanni Natanegara, Bayesian Applications in Pharmaceutical Development, 2019
The posterior predictive distribution for the Hill parameter, λ, is a rescaled beta distribution which is restricted to the range (0, 6): λ ∼ 6 × Beta(3.03, 18.15). The distribution is concentrated near 1 with a median value of 0.79. It assigns low probability to steep dose response curves with λ > 3. The predictive distribution for the ED50 was normalized by dividing the ED50 by its predicted value at the time the phase II study is planned. This prediction is denoted by P50. Some typical sources of information for this prediction are illustrated in the example in Section 6.3. These early predictions of the ED50 are a necessary part of early drug development, as they are required for decisions about what doses to manufacture. If a formal P50 is not available, past experience suggests that the midpoint between the two lowest (non-placebo) available doses is a useful proxy for the implied predicted potency. The posterior predictive distribution for the ED50/P50 for a new compound is a log-t distribution: log(ED50/P50) ∼ 0.6t3 + 0.79. The λ and ED50 parameters estimated from the same data for the same compound are often highly dependent in the posterior distribution, but the posterior distribution of the hierarchical parameters is approximately independent, so the λ and ED50 parameters are approximately independent in their posterior predictive distribution.
Standardization of Herbal Drugs
Published in Ravindra Kumar Pandey, Shiv Shankar Shukla, Amber Vyas, Vishal Jain, Parag Jain, Shailendra Saraf, Fingerprinting Analysis and Quality Control Methods of Herbal Medicines, 2018
Ravindra Kumar Pandey, Shiv Shankar Shukla, Amber Vyas, Vishal Jain, Parag Jain, Shailendra Saraf
This is the simplest bioassay, which produces an “All or None” response in different animals. In this bioassay, the pharmacological effect produced by the threshold dose of the sample is determined and compared with the standard drug or solution. Determination of LD50 (LD = Lethal dose) or ED50 (ED = effective dose) is done by this method, for example, cardiac arrest produced by digitalis in cats, hypoglycemic convulsions in mice, and so on.
Differences between the quality aspects of various generic and branded docetaxel formulations
Published in Current Medical Research and Opinion, 2021
Over the years, various approaches for assessing the bioequivalence of narrow therapeutic index drugs (NTIDs) have been implemented by various regulatory authorities among healthy volunteers (Table 2). Considering that the bioequivalence limit of 80.0% to 125.0% may be too wide for a standard 90% confidence interval, few regulatory authorities have taken the approach of directly narrowing the average bioequivalence limits30. NTIDs commonly applies to pharmaceutical drugs with minor variations in dosage or plasma concentration, which may amount to extreme treatment failure and/or adverse drug reactions, that may be life-threatening or lead to permanent or significant disability30. The CFR defines drugs with therapeutic index (TI) of ≤2 as NTIDs, that is, median lethal dose (LD50) and median effective dose (ED50) values differ by ≤2-fold or the minimum toxic plasma concentration and minimum effective blood concentration differ by ≤2-fold6. In addition to the US FDA, other regulatory agencies also pay special attention to this class of drugs. For instance, the Pharmaceutical and Food Safety Bureau of Japan defines NTIDs as narrow therapeutic range drugs; Health Canada defines this class of drugs using the critical dose drugs, and others regulatory agencies consider them as narrow therapeutic window and low therapeutic index26,27,29,31,32.
Synergistic effect of ursolic acid and piperine in CCl4 induced hepatotoxicity
Published in Annals of Medicine, 2021
Sayan Biswas, Amit Kar, Nanaocha Sharma, Pallab K. Haldar, Pulok K. Mukherjee
Isobologram method and the median effect method proposed by Chou and Talalay were used to analyze the interaction between combinations of UA and PIP [31]. In this method, the different dose combinations of UA + PIP were plotted against their respective effects (ED50, ED75 and ED90) in the form of percent hepatoprotective effect as mentioned in Equation 1. Here ED50 stands for median effective dose whereby the desired therapeutic effect produced is 50% [32]. Similarly, ED75 and ED90 stand for the therapeutic effect of 75% and 90% respectively. The doses are then connected through the line of additivity. A combination was taken as synergistic, antagonistic or additive when the observed dose combination falls below, above or on the line of additivity respectively. An extended combinational effect (synergism, antagonism, additivity) for UA and PIP was also determined by median effect analysis of Chou Talalay using COMPUSYN software 2.0 to obtain a combination index, a quantitative measure of synergism. The combination index (CI) values of less than 0.3 indicate strong synergism, the value of 0.3–0.69 indicates synergism, 0.70–0.84 indicates moderate synergism, 0.85–0.89 indicates mild synergism, 0.9–1.09 indicates additive effect, 1.10–1.19 indicates slight antagonism, 1.20–1.44 indicates antagonism, >1.45 indicates moderate strong antagonism [33].
Design, synthesis and biological evaluation of N-substituted α-hydroxyimides and 1,2,3-oxathiazolidine-4-one-2,2-dioxides with anticonvulsant activity
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Laureano L. Sabatier, Pablo H. Palestro, Andrea V. Enrique, Valentina Pastore, María L. Sbaraglini, Pedro Martín, Luciana Gavernet
ED50 value was calculated for compound 1g, since it showed strong anticonvulsant action at both doses evaluated in MES test. Again, we followed the standard procedures for the calculation, described in the Materials and Methods section. Essentially, ED50 measures the dose of drug that is effective in 50% of the tested animals9. This value is calculated at the time of peak effect (TPE), which has to be previously identified9. The final ED50 value of 1g was 29 mg/kg, which is equivalent to 0,106 mmol/kg (TPE = 0.5 h). This result is interesting in terms of potency, since it is in the range of ED50 values measured for classical ACDs in the same test. For example, phenytoin showed ED50 values of 0.0218 mmol/kg; whereas valproic acid, a representative ACD of broad spectrum, showed an ED50 value of 1.962 mmol/kg. Also important is the fact that all the structures passed the Rotorod test, which detects neurotoxicity in terms of sedation or ataxia; and none of the mice treated with the compounds died during the assays.