Drug stimuli-responsive

The ability to reduce stimulus-response mechanisms to single mono tonic functions allows relative cellular response to yield receptor-specific drug parameters. 

There are a number of assay formats available to test drugs in a functional mode. As discussed in Chapter 2, a main theme throughout the various stimulus-response cascades found in cells is the amplification of receptor stimulus occurring as a function of the distance, in biochemical steps and reactions, away from the initial receptor event. Specifically, the further down the stimulus-... 

Previously, pharmacologists were constrained to the prewired sensitivity of isolated tissues for agonist study. As discussed in Chapter 2, different tissues possess different densities of receptor, different receptor co-proteins in the membranes, and different efficiencies of stimulus-response mechanisms. Judicious choice of tissue type could yield uniquely useful pharmacologic systems (i.e., sensitive screening tissues). However, before the availability of recombinant systems these choices were limited. With the ability to express different densities of human target proteins such as receptors has come a transformation in drug discovery. Recombinant cellular systems can now... 

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. 

In 2000, the first example of ELP diblock copolymers for reversible stimulus-responsive self-assembly of nanoparticles was reported and their potential use in controlled delivery and release was suggested [87]. Later, these type of diblock copolypeptides were also covalently crossUnked through disulfide bond formation after self-assembly into micellar nanoparticles. In addition, the encapsulation of l-anilinonaphthalene-8-sulfonic acid, a hydrophobic fluorescent dye that fluoresces in hydrophobic enviromnent, was used to investigate the capacity of the micelle for hydrophobic drugs [88]. Fujita et al. replaced the hydrophilic ELP block by a polyaspartic acid chain (D ). They created a set of block copolymers with varying... 

ELP-based triblock copolypeptides have also been used to produce stimulus-responsive micelles, and Chaikof and coworkers envisioned the possible application of these micelles as controlled drug delivery vehicles. These amphiphilic triblock copolymers were constructed from two identical hydrophobic ELP endblocks and a hydrophilic ELP midblock. Below the transition temperature, loose and monodispersed micelles were formed that reversibly contracted upon heating, leading to more compact micelles with a reduced size [90]. 

Medical treatments in psychiatry generally do not follow the rule of stimulus-response specificity. Although the particular mechanism of drug action may be identified, the same medication given to two depressed patients, for example, may affect them very differently. Some of these differences may be traced to variations in metabolism from individual to individual (see chapter 3). Or the underlying biochemical abnormality in one depressed patient may be different than the abnormality in another depressed patient, and thus the medications affect different underlying disorders. 

When medications are given, especially if they are offered or recommended early on in treatment, many clients perception is "They just want to drug me. They don t want to talk. .. They don t want to hear my pain." Patients may feel they are being treated as a "case" (as in stimulus-response specificity) and the result can be a serious warp in the developing therapeutic alliance or even premature termination of therapy. 

Systemic administration of classical antipsychotics or clozapine block amphetamine-induced discriminative stimulus responses in the rat (205,206). The amphetamine response can also be blocked by direct injection of the drug into the nucleus accumbens (207). While classical antipsychotics completely inhibit the response, clozapine and olanzapine are somewhat less active, risperidone and remoxipride are weakly active, and sertindole and quetiapine were inactive (208, 209). Based on these findings, it has been proposed that the antagonism of the amphetamine discriminative stimulus response may be an indication of neuroleptic-induced deficit properties (209). Antipsychotic drugs also seem to inhibit the discriminative stimulus effects of hallucinogenic 5-HT agonists like DOI, DOM, and LSD in proportion to their 5-HT antagonist potencies (209-211). 

Soppimath KS, Aminabhavi TM, Dave AM, Kumbar SG, Rudzinski WE. Stimulus-responsive smart hydrogels as novel drug delivery systems. Drug Dev Ind Pharm 2002 28 957-974. 

Zha, L. Banik, B. Alexis, F. Stimulus responsive nanogels for drug delivery. Soft Matter 2011, 7 (13), 5908-5916. 

K.S. Soppimath, T.M. Aminabhavi, A.M. Dave, S.G. Kumbar, W.E. Rudzinski, Stimulus-responsive Smart hydrogels as novel drug dehvery systems. Drug Dev. Ind. Pharm. 28 (8) (2002) 957. 

Micelles Small size should help avoid nonspecific uptake Can be made stimulus responsive Instability, dose dumping Only suitable for delivering hydrophobic drugs Burt eta/. (1999) Gaucher eta/. (2005) Y. Baeeta/. (2005)... 

Yan Q, Yuan JY, Zhang FB, Sui XF, Xie XM, Yin YW, Wang SF, Wei Y (2009) Cellulose-based dual graft molecular brushes as potential drug nanocarriers stimulus-responsive micelles, self-assembled phase transition behavior, and tunable crystalline morphologies. Biomacromolecules 10 2033-2042... 

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