Cumulative dose-response curves

Wenger, G.R. Cumulative dose-response curves in behavioral pharmacology. Pharmacol Biochem Behav 13 647-651, 1980. 

Brading We never use cumulative dose—response curves. If these are used, they are different to curves based on non-cumulative addition. 

FIGURE 1-4 Cumulative dose-response curve. The median effective dose CED5tl) is 10 mg, and the median toxic dose (TD50] is 320 mg. The therapeutic index (Tf) for this drug is 32. 

Van Rossum JM, van den Brink (1963) Cumulative dose-response curves. Arch Int Pharmacodyn 143 240-246 Vassilev P, Radomirov R (1992) Contractile effects of prostaglandin E2 in rat rectum sensitivity to the prostaglandin antagonists diphloretin and SC 19220. Prostaglandins 44 471-484... 

Liu and Feng demonstrated that butylphthalide (30) competitively right-shifted the cumulative dose-response curve of noradrenaline-induced contraction while non-competitively right-shifting that of KC1 in isolated rat tail artery [353]. Phthalide 30 also inhibited noradrenaline-sensitive internal Ca2+ stores more selectively than noradrenaline-mediated external Ca2+ entry [353]. 

I/O ratios for the 1.5-pm aerosol ranged from 2.1 1 to 3.2 1. In contrast, the I/O ratio for the 3.3-pm aerosol ranged between 3.4 1 to 8.0 1. In 3 of 6 patients, Ruffin found that the cumulative dose-response curves and the ED q for the 3.3-pm aerosol were significantly shifted to the left of the 1.5-pm aerosol curves. EDjq is the effective dose that caused 50% of the maximum possible response. An example of this shift in the dose-response curve for one of the subjects is shown in Fig. 6. 

Minimum alveolar concentration is the percent of the agent required to provide surgical anesthesia to 50% of the population in terms of a cumulative dose-response curve. Hie lower the MAC, the more potent is the agent. 

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. 

A complete dose-response curve is produced by plotting the cumulative mean response at each dose. Error bars are drawn at cr around the mean. A typical result is shown in Figure 2-6. 

Paul They tend to be greater. If you give a dose of 10 fiM by itself and then work up to 10, uM, it is always much greater in the cumulative dos -response curve. 

The lARC has concluded that epidemiological studies have established the relationship between benzene exposure and the development of acute myelogenous leukemia and that there is sufficient evidence that benzene is carcinogenic to humans. Although a benzene-leukemia association has been made, the exact shape of the dose-response curve and/or the existence of a threshold for the response is unknown and has been the source of speculation and controversy. Some risk assessments suggest exponential increases in relative risk (of leukemias) with increasing cumulative exposure to benzene. At low levels of exposure, however, a small increase in leukemia mortality cannot be distinguished from a no-risk situation. In addition to cumulative dose other factors such as multiple solvent exposure, familial connection, and individual sus-... 

The quantal dose-response curve is actually a cumulative plot of the normal frequency distribution curve. The frequency distribution curve, in this case relating the minimum protective dose to the frequency with which it occurs in the population, generally is bell shaped. If one graphs the cumulative frequency versus dose, one obtains the sigmoid-shaped curve of Figure 22A. The sigmoid shape is a characteristic of most dose-response curves when the dose is plotted on a geometric, or log, scale. 

Those animals or patients responding at the lowest doses (Fig. 2.5) are more sensitive (hypersensitive) and those responding at the highest doses are less sensitive than the average (hyposensitive). The median point of the distribution is the dose where 50% of the population has responded and is the midpoint of the dose-response curve (Fig. 2.6). If the frequency distribution of the response is plotted cumulatively, this translates into a sigmoid curve. The more perfect the Gaussian curve, the closer to a true sigmoid curve will the dose-response curve be. 

Figure 6.6 shows a generalized dose-response curve. Such a plot may be obtained, for example, by administering different doses of a poison in a uniform manner to a homogeneous population of test animals and plotting the cumulative percentage of deaths as a function of the log of the dose. The result is normally an S-shaped curve, as shown in Figure 6.6. The dose corresponding to the midpoint (inflection point) of such a curve is the statistical estimate of the dose that would cause death in 50% of the subjects and is designated as LD50. The estimated doses at which 5% (LD5)...

Data analysis is done by the method of Litchfield and Wilcoxon. Mean dose - response curves are plotted on log-probit paper. Best fit to straight lines on these scales is determined by computerized regression. The cumulative ED50 values for vagal and sympathetic inhibition and the cumulative ED95 values for neuromuscular blockade are determined from the lines and 95 % confidence limits are calculated. Differences in potency are considered significant when P < 0.05. 

The efficacy and safety of salbutamol inhaled using a dry powder inhaler has been compared with salbutamol inhaled using a pressurized metered-dose inhaler (pMDI) in a randomized, open, crossover study in 12 patients with moderate to severe asthma. A total of 1600 micrograms of salbutamol was given on two separate days in a cumulative dose fashion in increments of 100,100,200, 400, and 800 micrograms at 3-minute intervals. FEVi rose progressively with each increment. The dose-response curves showed that powdered salbutamol was 3.0 times as potent (Cl = 1.8,5.8) as salbutamol from... 

Many industries regularly conduct repeat insult patch tests on human volunteers to evaluate topical irritancy. Groups of human volunteers are patched with test substance. One to five concentrations can be tested simultaneously, a wide enough range to yield results relevant to the usage. Cumulative skin irritancy is measured by applying patch applications each day for 3 weeks. Skin irritation is usually assessed visually, but blood flow and skin temperature can be measured objectively by laser Doppler flowmetry, ultrasound Doppler, heat flow disk measurement, sensitive thermocouple devices, or noncontact infrared radiative techniques. In these tests, dose-response curves can be obtained. Skin thickness can be measured with calipers as a measure of edema formation. 

Comparison of dose-response curves-1. One of the primary goals of toxicity testing is the comparison or ranking of toxicity. The cumulative plots comparing compound 1 and compound 2 demonstrate the distinct nature of the two different toxicity curves. 

Comparison of dose-response curves-3. Cumulative toxicity plots for compounds 1 and 3. Notice that the plots intersect at roughly 50% mortality. 

Thus, the type of exposure, continuous for lifetime versus intermittent or short-term exposure, appears to strongly influence the low dose-response curve. The cumulative exposure of 2 mmol/kg yielded a 92% liver cancer incidence... 

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