Concentration-effect curve

Giralclo, J., Vivas, N. M., Vila, E., and Baclia, A. (2002). Assessing the (a)symmetry of concentration-effect curves Empirical versus mechanistic models. Pharmacol. Therap. 95 21-45. 

Figure 11 Concentration-effect curves for derivative 1u and PD81,723. Enhancement of 100% is expressing the maximum decrease in [3H]CCPA dissociation by the highest concentration of 1u.

Concentration-effect curves of agonists at Torpedo nAChR expressed in oocytes. Potency of ligands suber-yldicholine ( ) > acetylcholine ( ) > PTMA (O) (unpublished observations)... 

Fig. 15. Relationship between the alfentanil plasma concentrations and the probability of needing naloxone to restore adequate spontaneous ventilation. The diagram at the upper part shows the alfentanil plasma concentrations of the patients who required naloxone (upward deflection) or did not require naloxone (downward deflection). The plasma concentration-effect curve for this clinical endpoint (lower part) was defined from the quantal data shown in the upper diagram using logistic regression. Bars indicate SE of C5o%. (From Ausems ME, Hug CC, Stanski DR, Burm AGE. Plasma concentrations of alfentanil required to supplement nitrous oxide anaesthesia for general surgery. Anaesthesiology 1986 65 362-73, reproduced by permission.)...

Concentration-Effect Curves Receptor Binding of Agonists... 

Until now we have considered receptor interactions and drug effects in terms of equations and concentration-effect curves. We must also understand the molecular mechanisms by which a drug acts. Such understanding allows us to ask basic questions with important clinical implications ... 

A) Representative experiment showing the effect of ethanol on non-NMDA reseptor-mediated response. (B) Representative experiment showing die influence of crocin on ethanol-induced inhibition of non-NMDA response. Crocin (10 iM) was applied 10 min prior to ethanol (white bar). (C) Concentration-effect curves for ethanol inhibition of non-NMDA response in the absence (O) or presence ( ) of 10 pM crocin. 

In order to confirm the possible interaction of ethanol and crocin on NMDA receptors, we also performed whole-cell patch recording with primary cultured hippocampal neurons and measured membrane currents induced by the application of NMDA in a voltage-clamped condition. Application of 100 pM NMDA induced an inward current of 100.2 9.8 pA (n=10) at a holding potential of -60 mV. The NMDA-induced inward current was not affected by 10 pM CNQX (data not shown), but was completely abolished by 30 pM APV, supporting the fact that the response was mediated by NMDA receptors. Ethanol inhibited NMDA-induced currents in a concentration-dependent manner. Crocin (10 pM) had no effect on NMDA-induced currents by itself (data not shown), but attenuated the inhibitory effect of ethanol on NMDA-induced currents. The concentration-effect curve for ethanol was shifted to the right by the presence of crocin [22]. 

Figure 5.3. Noradrenaline cumulative concentration-effect curves from guinea-pig hypoxic portal vein [21 Ij. All tissues were maintained in glucose-free physiological salt solution in hypoxic conditions. The vertical axis shows the mean force of contraction in response to each noradrenaline concentration on the horizontal axis. The statistical significance of differences between control (n = 20) and vitamin-E-treated (n = 25) muscle responses is shown by, P < 0.001. Vertical lines indicate the standard errors...

It is possible to use a preliminary dilution step of 1 100 when the pT-scale relies, for instance, on a < 20% effect endpoint measurement (e.g., determination of IC < 20 in non quantal tests with algae and bacteria). In this case, the pT-value should be calculated from the concentration-effect curve. The pT-value is determined by using the first sample concentration that generates an effect below 20%. If, for example, the concentration incurring a 19% effect is equated with a dilution factor of 1 3200, the pT-value is calculated with equation 5 as demonstrated below. The modulus for transforming decadic logarithms into binary ones, 1 / logio 2 , yields equation 6. For the 1 100 diluted wastewater example above, the pT-value can then be calculated with the help of equation 8. 

Figure 2. Probit transformation of the sigmoidal concentration-effect curves of Figure 1 for calculation of effective concentrations as IC50, IC20, or IC19.

Risk is generally considered as a product of the probability of an adverse effect and the magnitude of that effect. In ecotoxicology, risk depends on the probability and intensity of exposure and the sensitivity of the exposed organisms, whereby the interpretation of risk can involve aspects of space and time and value judgments (e.g., believing that 1 species is more important than another). The sensitivity is often determined in laboratory toxicity tests, in which dose- or concentration-effect curves are established. Extrapolation methods exist for both components of risk and the additional aspects. 

In other cases, the UFs are multiplied, usually yielding low hazardous concentration values that are supposed to offer sufficient protection in worst-case conditions. In mixture assessments, the simple generic model consists of the use of point estimates from concentration-effect curves, in combination with the concentration addition model, to address mixture problems. 

Figure 6.7 Concentration-effect curves of (0) A in the absence of B (I) A in the presence of B and (2) A in the presence of three times the amount of B used for curve I.

IC50 values (50 % inhibition of aggregation) are determined from the concentration-effect curves. 

Tier 1 involves the application of a simplified form of CA. It boils down to calculating the ratio between the exposure concentration of each component and a point estimate from its concentration-effect curve (e.g., the EC10, EC50, or NOEC), and the summation of these ratios. The human variant of this approach is the HI, and... 

---