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发布于:2018-8-10 17:10:23  访问:50 次 回复:0 篇
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Hereby decreasing the concentration variety in which drug two is superior to
Even though these models can offer an empirical basis for understanding the pharmacodynamics and activity of antiretroviral therapy, they can‘t offer mechanistic insight because HIV viral kinetics usually do not meet a lot of of your significant assumptions that underlie these models. Right here we present a very simple and general mechanistic model of HIV interaction with antiretroviral drugs that requires into account the kinetics with the HIV viral life cycle. We‘ve lately argued that the phase of the viral life cycle where a drug acts may have vital implications for clinically observed viral dynamics [7]. Experiments in vitro have confirmed our argument [6].Here, we demonstrate that the kinetics of your viral life cycle could also effect the pharmacodynamic properties of antiretroviral drugs. Extra broadly, we show that the IC50 of a drug is impacted by 3 categories of components: (i) drug-intrinsic properties PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28045099 associated to binding of drug to target, (ii) the kinetics of your stage of your viral life cycle at which the drug acts, and (iii) the kinetics of an infected cell that PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28827318 has been successfully inhibited. The theoretical framework provided by our model may be helpful for gaining insight into either drug-intrinsic or -extrinsic elements when details in regards to the other is readily available. Moreover, we have employed the mathematical connection among these factors that decide drug IC50 to quantify the drug-intrinsic properties (such as the strength and rate of interaction among an antiretroviral drug and its target) reflected by our model parameter kdrug for 22 unique antiretroviral drugs. In contrast to experimentally measured IC50, we find that kdrug correlates pretty well with experimentally measured purchase CS-5133 antiviral activity for these drugs, as reflected by IIP. The mathematical underpinning of this correlation lays inside the strong correlation we demonstrate amongst IIP along with the parameter m. On the other hand, future experiments, which empirically fit the approximate worth of kdrug to doseresponse information applying the connection funaffected = 1/[1 +kdrugcm/(pre+kHIV)] (based on.Hereby decreasing the concentration variety in which drug two is superior to drug 1 (Figure 4A). The effect of decreasing IC50 on lowering this f unaffected is ideal when [m2 +m1 (m2 -m1 )]/m1 m2 m1 m2 /(m2 -m1 ) 1 . Even so, IC502 >> IC501 even for the basic case of a protease inhibitor like nelfinavir with m = 1.81 and IC50 = 0.1668 M in comparison to an nRTI like abacavir with m = 0.95 and IC50 = 0.0344 m, funaffected is usually lowered by 75 when the IC50 of abacavir is lowered by half (Figure 4B).1/(m2 -m1 ) . IC50m2 /IC50m1 2Discussion Continued progress in treatment of HIV infection depends not just on improvement of new antiretroviral drugs but in addition on full understanding of how these drugs act. Such insight will allow for pharmacologic interventions that may further enhance the action of recognized antiretroviral drugs. Recent experimental advances, which include the development of direct single round infection assays [4,25] that usually do not endure in the unreliability of indirect or multiround assays [26,27] have provided a much better understanding in the pharmacodynamic properties for accessible antiretroviral drugs.
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