The number of therapeutic drugs known to be human teratogens is actually relatively small. This may reflect the rigorous animal testing and well defined labelling. Some of these drugs were identified ...to have reactive metabolites and this has been postulated, historically, to be their teratogenic mechanism. These drugs include thalidomide, various anticonvulsants and retinoic acid derivatives.Many of these experiments were conducted in a period where chemically reactive metabolites were being intensely investigated and associated with all forms of toxicity. The legacy of this is that these examples are routinely cited as well established mechanisms.Examination of mechanism leads to the conclusion that the teratogenicity in humans of these compounds is likely due to the primary and secondary pharmacology of the parent drug and stable circulating metabolites and that association of reactive metabolites to this toxicity is unwarranted.The number of therapeutic drugs known to be human teratogens is actually relatively small. This may reflect the rigorous animal testing and well defined labelling. Some of these drugs were identified to have reactive metabolites and this has been postulated, historically, to be their teratogenic mechanism. These drugs include thalidomide, various anticonvulsants and retinoic acid derivatives.Many of these experiments were conducted in a period where chemically reactive metabolites were being intensely investigated and associated with all forms of toxicity. The legacy of this is that these examples are routinely cited as well established mechanisms.Examination of mechanism leads to the conclusion that the teratogenicity in humans of these compounds is likely due to the primary and secondary pharmacology of the parent drug and stable circulating metabolites and that association of reactive metabolites to this toxicity is unwarranted.
Clearance in Drug Design Smith, Dennis A; Beaumont, Kevin; Maurer, Tristan S ...
Journal of medicinal chemistry,
2019-Mar-14, Letnik:
62, Številka:
5
Journal Article
Recenzirano
Due to its implications for both dose level and frequency, clearance rate is one of the most important pharmacokinetic parameters to consider in the design of drug candidates. Clearance can be ...classified into three general categories, namely, metabolic transformation, renal excretion, and hepatobiliary excretion. Within each category, there are a host of biochemical and physiological mechanisms that ultimately determine the clearance rate. Physiochemical properties are often indicative of the rate-determining mechanism, with lipophilic molecules tending toward metabolism and hydrophilic, polar molecules tending toward passive or active excretion. Optimization of clearance requires recognition of the major clearance mechanisms and use of the most relevant in vitro and in vivo tools to develop structure-clearance relationships. The reliability of methods to detect and predict human clearance varies across mechanisms. While methods for metabolic and passive renal clearance have proven reasonably robust, there is a clear need for better tools to support the optimization of transporter-mediated clearance.
Data from in vitro plasma protein binding experiments that determine the fraction of protein-bound drug are frequently used in drug discovery to guide structure design and to prioritize compounds for ...in vivo studies. However, we consider that these practices are usually misleading, because in vivo efficacy is determined by the free (unbound) drug concentration surrounding the therapeutic target, not by the free drug fraction. These practices yield no enhancement of the in vivo free drug concentration. So, decisions based on free drug fraction could result in the wrong compounds being advanced through drug discovery programmes. This Perspective provides guidance on the application of plasma protein binding information in drug discovery.
Relevance of Half-Life in Drug Design Smith, Dennis A; Beaumont, Kevin; Maurer, Tristan S ...
Journal of medicinal chemistry,
05/2018, Letnik:
61, Številka:
10
Journal Article
Recenzirano
Drug half-life has important implications for dosing regimen and peak-to-trough ratio at the steady state. A half-life of 12-48 h is generally ideal for once daily dosing of oral drugs. If the ...half-life is too short, it may require more frequent dosing in order to maintain desired exposures and avoid unnecessarily high peak concentrations. This may pose challenges to achieving optimal efficacy, safety, and patient compliance. If the half-life is too long, the time over which accumulation and subsequent elimination occur may be prolonged. This may pose problems with managing adverse effects and the design of efficient clinical trials. Half-life is a key parameter for optimization in research and development. Structural modification to affect clearance, and to a lesser extent volume of distribution, is the preferred means of modulating half-life. An effective approach to half-life optimization requires an understanding of the many pitfalls associated with its estimation and interpretation.
Volume of Distribution in Drug Design Smith, Dennis A; Beaumont, Kevin; Maurer, Tristan S ...
Journal of medicinal chemistry,
08/2015, Letnik:
58, Številka:
15
Journal Article
Recenzirano
Volume of distribution is one of the most important pharmacokinetic properties of a drug candidate. It is a major determinant of half-life and dosing frequency of a drug. For a similar log P, a basic ...molecule will tend to exhibit higher volume of distribution than a neutral molecule. Acids often exhibit low volumes of distribution. Although a design strategy against volume of distribution can be advantageous in achieving desirable dosing regimen, it must be well-directed in order to avoid detrimental effects to other important properties. Strategies to increase volume of distribution include adding lipophilicity and introducing basic functional groups in a way that does not increase metabolic clearance.
The distribution of a drug within the body should be considered as involving movement of unbound drug between the various aqueous spaces of the body. At true steady state, even for a compound of ...restricted lipoidal permeability, unbound concentrations in all aqueous compartments (blood, extracellular, and intracellular) are considered identical, unless a compartment has a clearance/transport process. In contrast, total drug concentrations may differ greatly, reflecting binding or partitioning into constituents of each compartment. For most highly lipid permeable drugs, this uniform unbound concentration is expected to apply. However, many compounds have restricted lipoidal permeability and are subjected to transport/clearance processes causing a gradient between intracellular and extracellular unbound concentrations even at steady state. Additional concerns arise where the drug target resides in a site of limited vascularity. Many misleading assumptions about drug concentrations and access to drug targets are based on total drug. Correction, if made, is usually by measuring tissue binding, but this is limited by the lack of homogenicity of the organ or compartment. Rather than looking for technology to measure the unbound concentration it may be better to focus on designing high lipoidal permeable molecules with a high chance of achieving a uniform unbound drug concentration. It is hoped this paper will stimulate greater understanding of the path from circulation to cell interior, and thereby in part avoid or minimize the need to provide the experimentally very determining, and sometimes still questionable, answer to this problem.
•Corrosion protection of a tetrafunctional epoxy-amine coating.•Epoxy-amine coating exhibited high impedance after 30 d of NaCl immersion.•Artificially damaged epoxy-amine coatings displayed ...satisfactory performances.•Coating in pristine form can function as a high-performance protective material.
Epoxy resins are one of the most widely used thermosetting materials in industrial and practical applications because they exhibit excellent mechanical, thermal, and dielectric performance at commodity volume and cost. In particular, multifunctional epoxies—dense and cross-linked structured resins—are used as molding compounds, sealants, and protective coatings for many barrier-related applications. In this work, we used a tetrafunctional epoxy-amine resin as a coating for mild steel and used electrochemical impedance spectroscopy (EIS) to investigate its protection performance in a 3.5 wt % NaCl solution. The results indicate that the coating was able to resist corrosion and maintain a very high impedance modulus for more than 30 d of continuous exposure to the NaCl solution. Different resistance behaviors, as indicated by EIS, were observed for the coatings with artificially introduced damage. The coating also showed high thermal resistance and good adhesion to mild steel surfaces. This tetrafunctional epoxy-amine resin could effectively function as a high performance and corrosion resistant coating material for semiconductor, aerospace, and marine applications.
Future climate projections illuminate our understanding of the climate system and generate data products often used in climate impact assessments. Statistical downscaling (SD) is commonly used to ...address biases in global climate models (GCM) and to translate large‐scale projected changes to the higher spatial resolutions desired for regional and local scale studies. However, downscaled climate projections are sensitive to method configuration and input data source choices made during the downscaling process that can affect a projection's ultimate suitability for particular impact assessments. Quantifying how changes in inputs or parameters affect SD‐generated projections of precipitation is critical for improving these datasets and their use by impacts researchers. Through analysis of a systematically designed set of 18 statistically downscaled future daily precipitation projections for the south‐central United States, this study aims to improve the guidance available to impacts researchers. Two statistical processing techniques are examined: a ratio delta downscaling technique and an equi‐ratio quantile mapping method. The projections are generated using as input results from three GCMs forced with representative concentration pathway (RCP) 8.5 and three gridded observation‐based data products. Sensitivity analyses identify differences in the values of precipitation variables among the projections and the underlying reasons for the differences.Results indicate that differences in how observational station data are converted to gridded daily observational products can markedly affect statistically downscaled future projections of wet‐day frequency, intensity of precipitation extremes, and the length of multi‐day wet and dry periods. The choice of downscaling technique also can affect the climate change signal for variables of interest, in some cases causing change signals to reverse sign. Hence, this study provides illustrations and explanations for some downscaled precipitation projection differences that users may encounter, as well as evidence of symptoms that can affect user decisions.
Statistical downscaling techniques are frequently used to translate changes from global climate models to local scales. However, there is no standard practice with respect to downscaling technique or creating the gridded observations used for training. This study demonstrates that multiple precipitation variables are sensitive to the training observations and the downscaling technique. Depending upon the variable of interest and the application, end users of downscaled projections should consider these factors in their own efforts.
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