Dose effect/response curves

Comparative evaluation of anti-human thyroid stimulating hormone (hTSH) antibody, bound to the fifth-generation ammonia core (N5) or the fifth-generation ethylenediamine core (E5) dendrimer (1), did not show any differences in either the effective protein concentrations or the shape of the dose-dependent response curves (calibration curves) as determined from the recovery of standard controls. All the other experiments described here were thus carried out with the fifth-generation (i.e. dia. = 70 A) particles of ethylenediamine core (E5) de-ndrimers. The later particles were selected for their ability to be produced reproducibly on a large scale. 

To define the shape and location of the dose/concentration/response curves for both desired and undesired effects - preliminary assessment of benefit/risk... 

In theory, comparisons between dose-effecl/response curves and risk boundary curves which allow for differences in acceptable frequencies for effects of varying severity could be utilized, but, in practice concepts such as the no adverse effect level and safety... 

Venlafaxine and its active metabolite, 0-desmethylvenlafaxine (ODV), have dual mechanisms of action, with preferential affinity for 5-HT reuptake and weak inhibition of NE and dopamine reuptake. Venlafaxine is approximately 30 times more potent as an inhibitor of SERT than of NET (68). Because of the 30 times difference in transporter affinities, increasing the dose of venlafaxine from 75 to 375 mg/day can sequentially inhibit SERT and NERT. Thus, venlafaxine displays an ascending dose-dependent antidepressant response in contrast to the flat dose-antidepressant response curve observed with the SSRIs. This sequential action for venlafaxine also is consistent with its dose-dependent adverse-effect profile. Its mechanism of action is similar to imipramine. 

Fig. 5. Toxic chemical dose—response curves (a) no effect (b) linear effect (c) no effect at low dose and (d) beneficial at low dose.

To.xicity values for carcinogenic effects can be e.xprcsscd in several ways. The slope factor is usually, but not always, the upper 95th percent confidence limit of the slope of the dose-response curve and is e.xprcsscd as (mg/kg-day). If the extrapolation model selected is the linearized multistage model, this value is also known as the ql. That is ... 

If the exposure level (E) exceeds tliis tlireshold (i.e., E/RfD exceeds unity), tliere may be concern for potential noncancer effects. As a rule, tlie greater tlie value of E/RfD above unity, tlie greater tlie level of concern. However, one should not interpret ratios of E/RfD as statistical probabilities a ratio of 0.001 does not mean tliat tliere is a one in one tliousand cliance of the effect occurring. Furtlier, it is important to empliasize tliat tlie level of concern does not increase linearly as tlie RfD is approached or exceeded because RfDs do not have equal accuracy or precision and are not based on tlie same severity of toxic effects. Thus, tlie slopes of the dose-response curv e in excess of the RfD can range widely depending on tlie substance. 

FIGURE 2.18 Inotropic and lusitropic responses of guinea pig left atria to (3-adrenoceptor stimulation. Panels A to C isometric tension waveforms of cardiac contraction (ordinates are mg tension abscissae are msec), (a) Effect of 0.3 nM isoproterenol on the waveform. The wave is shortened due to an increase in the rate of diastolic relaxation, whereas no inotropic response (change in peak tension) is observed at this concentration, (b) A further shortening of waveform duration (lusitropic response) is observed with 3 nM isoproterenol. This is concomitant with positive inotropic response (increase maximal tension), (c) This trend continues with 100 nM isoproterenol, (d) Dose-response curves for ino tropy (filled circles) and lusitropy (open circles) in guinea pig atria for isoproterenol, (e) Dose-response curves for inotropy (filled circles) and lusitropy (open circles) in guinea pig atria for the P-adrenoceptor partial agonist prenalterol. Data redrawn from [6]. 

FIGURE 3.6 Classical model of agonism. Ordinates response as a fraction of the system maximal response. Abscissae logarithms of molar concentrations of agonist, (a) Effect of changing efficacy as defined by Stephenson [24], Stimulus-response coupling defined by hyperbolic function Response = stimulus/(stimulus-F 0.1). (b) Dose-response curves for agonist of e = 1 and various values for Ka. 

FIGURE 5.4 Microphysiometry responses of HEK 293 cells transfected with human calcitonin receptor, (a) Use of microphysiometry to detect receptor expression. Before transfection with human calcitonin receptor cDNA, HEK cells do not respond to human calcitonin. After transfection, calcitonin produces a metabolic response, thereby indicating successful membrane expression of receptors, (b) Cumulative concentration-response curve to human calcitonin shown in real time. Calcitonin added at the arrows in concentrations of 0.01, 0.1, 1.10, and lOOnM. Dose-response curve for the effects seen in panel B. 

FIGURE 5.10 Effects of co-expressed G-protein (G ) on neuropeptide NPY4 receptor responses (NPY-4). (a) Dose-response curves for NPY-4. Ordinates Xenopus laevis melanophore responses (increases light transmission). Ordinates logarithms of molar concentrations of neuropeptide Y peptide agonist PYY. Curves obtained after no co-transfection (labeled 0 jig) and co-transfection with cDNA for Gai6. Numbers next to the curves indicate jig of cDNA of Ga]g used for co-transfection, (b) Maximal response to neuropeptide Y (filled circles) and constitutive activity (open circles) as a function of pg cDNA of co-transfected G g. 

By utilizing complete dose-response curves, the method devised by Barlow, Scott, and Stephenson [9] can be used to measure the affinity of a partial agonist. Using null procedures, the effects of stimulus-response mechanisms are neutralized and receptor-specific effects of agonists are isolated. This method, based on classical or operational receptor theory, depends on the concept of equiactive concentrations of drug. Under these circumstances, receptor stimuli can be equated since it is assumed that equal responses emanate from equal stimuli in any given system. An example of this procedure is given in Section 12.2.1. 

FIGURE 5.16 The effect of desensitization on stop-time mode measurements. Bottom panels show the time course of response production for a system with no desensitization, and one in which the rate of response production fades with time. The top dose response curves indicate the area under the curve for the responses shown. It can be seen that whereas an accurate reflection of response production is observed when there is no desensitization the system with fading response yields an extremely truncated dose-response curve. 

The Furchgott method can be effectively utilized by fitting the dose-response curves themselves to the operational model with fitted values of x (before and after alkylation) and a constant KA value. When fitting experimental data, the slopes of the dose-response curves may not be unity. This is a relevant factor in the operational model since the stimulus-transduction function of cells is an integral part of the modeling of responses. Under these circumstances, the data is fit to (see Section 3.13.3 and Equation 3.49)... 

FIGURE 6.1 Effects of antagonists on agonist dose-response curves, (a) Surmountable antagonism with no diminution of maxima and no limiting antagonism (competitive antagonists). 

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