Efficacy, defined

Drug response depends on both the affinity of a drug for its receptors (defined below) and the drug s efficacy (defined in the next section). 

Effectiveness characteristics considered desirable in healthcare antiseptic drug products are described in Table 4, and the requirements for assessment of efficacy depend on the indication sought. The methods used to examine these product characteristics are controversial since many methods are available to assess efficacy and each may produce different outcomes with the same product. Also lacking is interpretation of the data obtained from these test methods. The relationship of the outcome measure of efficacy defined by the test method and its relevance to the clinical setting is not well established. Efforts to close this gap are not forthcoming. Consequently, the FDA must use methods at its disposal to assess product efficacy. Thus, protocols whose purpose is to explore product characteristics and to assess whether the product meets the minimum efficacy requirements for an indication are recommended. Due to limitations associated with each of these test protocols, they cannot be used independently of each other but must be used in concert to gain an overall perspective of product efficacy. The in vitro assays are used to define the use of the antiseptic in a specific instance while the in vivo assays are used to define its use in a particular clinical setting. Ideally, both approaches must produce similar results, but this may not always be the case. Despite these limitations, preclinical and clinical simulation studies attempt to provide predictive evidence of clinical efficacy. 

However, maximum leceptoi occupancy for fuU agonists was still requited for maximum tissue response. The efficacy, was introduced through the concept of a stimulus, 3", defined as... 

It is truly possible to imagine the characteristics of an ideal radiopharmaceutical only in the context of a specific disease and organ system to which it might be appHed. Apart from the physical factors related to the radioisotope used, the only general characteristic that is important in defining the efficacy of these materials is the macroscopic distribution in the body, or biodistribution. This time-dependent distribution at the organ level is a function of many parameters which may be divided into four categories factors related to deUvery of the radiopharmaceutical to a particular tissue factors related to the extraction of the compound from circulation factors related to retention of the compound by that tissue and factors deterrnined by clearance. The factors in the last set are rarely independent of the others. 

In the first stages of the development of an Action plan all control options are considered. In the case of lakes, this process is aided by a PC-based expert system , PACGAP, which looks at the physical and chemical characteristics of the lake to determine the most likely option for control. Once further, more detailed information has been collected on the lake s nutrient inputs and other controlling factors, amore complex interactive model can be used (Phytoplankton Response To Environmental CHange, PROTECH-2) to define the efficacy of proposed control options more accurately. This model is able to predict the development of phytoplankton species populations under different nutrient and stratification regimes. 

While there are mairy variants of the basic, model, one can show that there is a well-defined minimal set of niles that define a lattice-gas system whose macroscopic behavior reproduces that predicted by the Navier-Stokes equations exactly. In other words, there is critical threshold of rule size and type that must be met before the continuum fluid l)cliavior is matched, and onec that threshold is reached the efficacy of the rule-set is no loner appreciably altered by additional rules respecting the required conservation laws and symmetries. 

Kauffman ([kauffSO], [kauffOOa]) has introduced a class of parametrizable fitness landscapes called NK-landscapes, that provide a formalism for studying the efficacy of GA evolution as a function of certain statistical properties of the landscape. Given N binary variables Xi = 1, so that x = (xi, X2, , Xjv) represents a vertex of an A -dimensional hypercube, an NK-landscape is defined by a fitness function, JF, of the form... 

FIGURE 3.5 Major components of classical receptor theory. Stimulus is the product of intrinsic efficacy (s), receptor number [R], and fractional occupancy as given by the Langmuir adsorption isotherm. A stimulus-response transduction function f translates this stimulus into tissue response. The curves defining receptor occupancy and response are translocated from each other by the stimulus-response function and intrinsic efficacy. 

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. 

The transducer function defines the efficiency of the system to translate receptor stimulus into response and defines the efficacy of the agonist. Specifically, it is the fitting parameter of the hyperbolic function linking receptor... 

Equation 6.19 predicts an increasing IC50 with either increases in L or 1. In systems with low-efficacy inverse agonists or in systems with low levels of constitutive activity, the observed location parameter is still a close estimate of the KB (equilibrium dissociation constant of the ligand-receptor complex, a molecular quantity that transcends test system type). In general, the observed potency of inverse agonists only defines the lower limit of affinity. 

AR] complex) interacts with an equilibrium association constant Ke (to yield an efficacy term x) and the allosterically altered agonist-bound receptor complex ([ABR] complex) interacts with the cell with equilibrium association constant K e (to yield an altered efficacy x7). It is useful to define a ratio of efficacies for the native and allosterically modulated receptor of x /x (denoted , where = x//x). 

Operational model, devised and published by James Black and Paul Leff (Proc. R. Soc. Lond. Biol. 220,141-162, 1983), this model uses experimental observation to describe the production of a physiological response by an agonist in general terms. It defines affinity and the ability of a drug to induce a response as a value of x, which is a term describing the system (receptor density and efficiency of the cell to convert an activated receptor stimulus into a response) and the agonist (efficacy). It has provided a major advance in the description of functional effects of drugs see Chapter 3.6 for further discussion. 

Efficacy is a parameter which describes the strength of a single drug-receptor complex in evoking a response from the cell or tissue. The intrinsic efficacy of a drag is a proportionality constant that defines the power of the drug to induce a response. 

To maximize safety and therapeutic efficacy, potential drugs are required to be highly specific for their protein target and orally bioavailable. In addition, for a drug candidate to reach the market, it must be patentably novel. A computational approach therefore needs to find novel compounds with well-defined pharmacological properties from the vast space of possible organic compounds ( chemical space ). 

The combined experience with IV rt-PA treatment beyond 3 hours, therefore, suggests reduced effectiveness compared to treatment within 3 hours. A pooled analysis of the ATLANTIS, ECASS, and NINDS rt-PA studies confirmed that the odds of a favorable 3-month outcome, defined as minimal or no poststroke disability on the BI, mRS, and NIHSS, decreased with increasing stroke onset to start of treatment time (OTT) (p = 0.005). The odds ratios for favorable outcome with rt-PA treatment were 2.8 (95% Cl 1.8. 5) for OTT 0-90 minutes, 1.6 (95% Cl 1.1-2.2) for 91-180 minutes, 1.4 (95% Cl 1.1-1.9) for 181-270 minutes, and 1.2 (95% Cl 0.9-1.5) for 271-360 minutes. This finding, that earlier treatment is associated with more therapeutic efficacy, supports the adage that in the delivery of acute stroke therapy time is brain. " The rate of sICH was not associated with OTT. ... 

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